NANOSCALE SCIENCE AND TECHNOLOGY

UNIT-I INTRODUCTION

1.1 Introduction
 The study of objects and phenomena at a very small scale, roughly 1-100 nanometers

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(nm)is called as Nanoscale science or Nanoscience.
o To understand how small one nm is let us see few comparisons
1. A Red blood cell is approximately 7000nm wide.
2. Water Molecule is almost 0.3nm across.
3. Human hair which is ~ 80,000nm wide.

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 Nanotechnology can be defined as the design, characterization, production and
application of structures devices and systems by controlling shape and size at a Nano
meter Scale.

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 In Nano science building blocks may consist of anywhere from a few hundred atoms to
millions of atoms.
 Nanometer scale: The length scale ranging from 1–100 nm where corresponding material
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properties are size & shape dependent.
 The properties of Nano Materials are very much different from those at a larger scale.
Two principal factors cause the properties of Nano Materials to differ significantly from
other materials.
1. Increased relative surface area.
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2. Quantum confinement effect: electrons can only exist at discrete energy

levels. Quantum dots are nanomaterials that display the effect of quantization
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of energy.
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 These factors can charge or enhance properties such as reactivity, strength and electrical
characteristics.

 Characteristics of Nanoscale materials:

o Fiber that is stronger than spider web

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o Metal 100 times stronger than steel and 1/6 of its weight
o Catalysts that respond more quickly and to more agents
o Plastics that conduct electricity.
o Coatings that are nearly frictionless –(Shipping Industry)
o Materials that change color and transparency on demand.

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o Materials that are self repairing, self cleaning, and never need repainting.
o Nanoscale powders that are five times as light as plastic but provide the same
radiation protection as metal.

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1.2 Implication for Physics, Chemistry, Biology and Engineering

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Living systems are governed by molecular behavior at the nanometer scale, where
chemistry, physics, biology, and computer simulation all now converge.

1.2.1 Implications for Physics:

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1. Nanoscale materials mass is extremely small and gravitational forces become negligible.
Instead electromagnetic forces are dominant in determining the behaviour of atoms and
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molecules.
2. Wave-Particle duality of matter: For objects of very small mass, such as the electron,
wavelike nature has a more pronounced effect. Similarly, nanoscale materials too exhibit
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wave behaviour.
3. Quantum confinement: In a nanomaterial, such as a metal, electrons are confined in space
rather than free to move in the bulk material. 2D quantum confinement leads to quantum
wire and 3D quantum confinement to quantum dot.
 4. Quantization of energy: electrons can only exist at discrete energy levels. Quantum dots
are nanomaterials that display the effect of quantization of energy.
Fig.

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5. Increased surface-to-volume ratio: One of the distinguishing properties of nanomaterials
is that they have an increased surface area.
Fig.

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6. Cooling chips or wafers to replace compressors in cars, refrigerators, air

conditioners and multiple other devices, utilizing no chemicals or moving parts.
7. Sensors for airborne chemicals or other toxins.
8. Photovoltaics (solar cells), fuel cells and portable power to provide inexpensive,
clean energy.
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9. Nanoparticle reinforced polymers (or) Nanocomposites:

Requirements for increased fuel economy in motor vehicles, demand the use of new,
light weight materials — typically plastics — that can replace metal. Nanocomposites, a
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new class of materials, consist of traditional polymers reinforced by nanometer-scale

particles dispersed throughout. These reinforced polymers present an economical
solution to metal replacement. These nanocomposites can be easily extruded or molded
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to near-final shape, provide stiffness and strength approaching that of metals, and reduce
weight. Corrosion resistance, noise dampening, parts consolidation, and recyclability all
would be improved. The weight reduction of motor vehicles from proposed potential
applications are expected to save fuel and thereby reduce carbon dioxide emissions. (~15
billion liters of gasoline is expected to be saved over the life of one year’s production of
 vehicles by the American automotive industry and thereby reduce carbon-dioxide
emissions by more than 5 billion kilograms).
10. Nanocomposite materials also find use in non-automotive applications such as pipes and
fittings for the building and construction industry; refrigerator liners; business, medical,
and consumer equipment housings; recreational vehicles; and appliances.

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11. The current generation of lithium ion batteries will be replaced by nanotechnology power
sources. Because lithium ion batteries work just fine for a cell phone used for the
occasional short phone call. However, if used to power future smart phones, such a
battery is likely to run down quite quickly. Nanotechnology will help enable new kinds of
power sources, such as better batteries, miniature fuel cells, and tiny photovoltaic panels

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that will have greater power densities than today’s batteries. It will also enable more
energy efficient components and sub-assemblies for mobile devices. For example, a new
generation of thin-film transistors built using organic molecules is enabling low-power

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plastic displays. Displays are typically the most power consuming subsystem in mobile
computing or communications equipment. In addition to saving power, nanotechnology
has the potential for bringing down the cost of mobile terminals and increasing the

1.2.2 Implication for Chemistry:

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quality of visual output from these terminals.

1. Nanomaterial is formed of at least a cluster of atoms or cluster of molecules. It follows

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all types of bindings that are important in chemistry which are important in Nanoscience.
They are generally classified as:
Intra-molecular bonding (chemical interactions): These are bondings that involve changes in
the chemical structure of the molecules. They include: ionic bonds, covalent bonds and
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metallic bonds;

Inter-molecular bonding (physical interaction): These are bondings that do not involve
changes in the chemical structure of the molecules. They include ion-ion and ion-dipole
interactions; Van der Waals interactions; hydrogen bonds; hydrophobic interactions;
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repulsive forces.

Nanomaterials often arise from a number of molecules held together or large molecules that
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assume specific three-dimensional structures through intermolecular bonding. In these

macromolecules intermolecular bonding often plays a crucial role. The bonds such as
hydrogen bonding and Van der Waals bonding are though weak, their total energy is quite
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large due to large number of interactions. Example: In the structure of DNA (nanoscale), the
two helixes are held together by numerous hydrogen bonds. This point becomes particularly
relevant in Nanoscience, where materials can have very large surface areas and consequently
small forces can be applied to very large areas.
 Intermolecular bondings often hold together macromolecules (proteins) in specific three
dimensional structures with which precise biological functions are associated.

2. Nanoscale particles exhibit greater equilibrium vapor pressures, chemical potentials and
solubility’s relative to bulk materials. This is due to high surface energy of such small

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particles. Anything that enhances the prospect of atomic/molecular motion also enhances
particle growth and aggregation which in turn is restricted by using molecular caps for
such nanostructures to terminate and stabilize the nanostructures.
3. Ionization potential increases as the transition-metal-atom cluster drops to nano scale.
This is mainly applied in heterogeneous catalysis. In chemistry, heterogeneous

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catalysis refers to the form of catalysis where the phase of the catalyst differs from that of
the reactants. Phase here refers not only to solid, liquid, vs gas, but also immiscible
liquids, e.g. oil and water.

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4. Developed by the oil industry, the ordered mesoporous material MCM-41 (known also as
“self-assembled monolayers on mesoporous supports,” SAMMS), with pore sizes in the
range of 10−100 nanometers, is now widely used for the removal of ultrafine
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contaminants.
5. Nanofluidics is the study of the behavior, manipulation, and control of fluids that are
confined to structures of nanometer (typically 1-100 nm) characteristic. Motivation to go
from micro-to nano-electronics drives scientist to integrate and miniaturize chemistry and
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to try to understand and manipulate smaller and smaller amounts of liquids. This is
essential when only small amounts of reactants are available. It also helps to better
control potentially toxic or explosive reactions. The idea is to integrate a complete
laboratory into a silicon waver or a plastic chip. Although this concept has not penetrated
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our everyday live to the same extent as microelectronics has, the first commercial
applications are meanwhile available, e.g., enzymatic analysis and DNA-sequencing. The
channels in which the substances are transported in existing devices have typical
diameters of 50-100 µm and are still macroscopic. Correspondingly this technique is
called microfluidics.
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6. A dendrimer is a synthetic, three-dimensional macromolecule. It is built up from a

monomer, with new branches added in steps until a tree-like structure is created
(dendrimer comes from the Greek dendra, meaning tree). The largest molecules ever
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made with an atomically defined structure are the dendrimer shown in the figure below.
It consists of precisely 5592 benzene rings and has a molecular mass of 546404 g/mol.
Dendrimers can not only be made large. They can also be made with specific functions,
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such as efficient fluorophores or as carriers, e.g. for drugs. The inner part of the
 dendrimer provides a defined environment, while the groups on the surface regulate the

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compatibility with the environment.

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7. Synthesis of nanoparticles : Many materials, which are relevant for novel energy cycles
and more efficient chemical reactions (catalysis) do not exist as nanostructures so that
“de novo” systems have to be designed from scratch. This for instance holds for metal

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carbide and nitride particles, which offer new pathways for metal/base catalysis. They
also hold the record in mechanical hardness and magnetization. In general, both size and
shape add to the favorable properties and must be controlled or adjusted.
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8. New cathode nanomaterials for the lithium battery are another target for novel
nanostructures where progress will directly impact society
9. Nanoparticles by design: Using emulsion droplets as nanoreactors for precipitation
Taylor-made nanoparticles with well defined size and shape are needed for new
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applications e.g. in surface physics, catalysis, and biomedicine. Emulsion-assisted
precipitation is a very attractive process technology for the production of Taylor-made
nanoparticles. In this approach, the droplets of microemulsions (droplet size 2 to 100 nm)
or miniemulsions (droplet size > 100 nm and < 1 µm) are used as reaction compartments
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to perform the precipitation of nanoparticles, initiated by a liquid-phase chemical reaction

which is followed by nucleation and growth of solid particles.
10. It is identified that ‘inertness” is not found in few chemical reactions of nanostructure
materials due to its high-reactivity character. So, strategies are made to stabilize the
nanostructured materials.
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11. The construction of nanostructures molecule-by-molecule introduces the distinct

advantage that organization and functionality can be manipulated by chemical design.
This refers to the spontaneous association of molecules under near-equilibrium conditions
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into stable, well-defined aggregates joined by non-covalent bonds. It is the key building
principle of all living matter and the basics of supramolecular chemistry.
12. Catalysis: A catalyst is a substance that increases a chemical reaction rate without
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being consumed or chemically altered. Nature’s catalysts are called enzymes and are
able to assemble specific and end-products, always finding pathways by which reactions
take place with minimum energy consumption. Man-made catalysts are not so energy
efficient. They are often made of metal particles fixed on an oxide surface, working on a
hot reactant stream. One of the most important properties of a catalyst is its active
 surface where the reaction takes place. The ‘active surface’ increases when the size of
the catalysts is decreased: the smaller the catalyst particles, the greater the ratio of
surface-to-volume. The higher is the catalysts’ active surface, the greater is the surface
reactivity. Research has shown that the spatial organization of the active sites in a
catalyst is also important. Both properties (nanoparticle size and molecular

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structure/distribution) can be controlled using nanotechnology. Hence, this technology
has great potential to expand catalyst design with benefits for the chemical, petroleum,
automotive, pharmaceutical and food industries. The use of nanoparticles that have
catalytic properties will allow a drastic reduction of the amount of material used, with
resulting economic and environmental benefits.

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13. Sustainability: Nanotechnology will improve agricultural yields for an increased
population, provide more economical water filtration and desalination, and enable
renewable energy sources such as highly efficient solar energy conversion; it will reduce
the need for scarce material resources and diminish pollution for a cleaner environment.
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For example, in 10 to 15 years, projections indicate that nanotechnology-based lighting
advances have the potential to reduce worldwide consumption of energy by more than
10%
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1.2.3 Implication for Biology:

1. Earlier difficult process of genome sequencing and detecting the genes’ expression can be
made dramatically more efficient through use of nanofabricated surfaces and devices.
2 Expanding our ability to characterize an individual’s genetic makeup have revolutionized
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diagnostics and therapeutics.

3 Nanotechnology can provide new formulations and routes for drug delivery, enormously
broadening the drugs’ therapeutic potential.
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4 Advanced drug delivery systems, including implantable devices that automatically

administering drugs and capable of sensoring drug level.
5 Medical diagnostic tools, such as cancer-tagging mechanisms and "lab-on-a-chip", real
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time diagnostics for physicians.

6 Basic studies of cell biology and pathology, to characterize the chemical and mechanical
properties of cells (including processes such as cell division and locomotion) and to
measure properties of single molecules.
7 Artificial inorganic and organic nanoscale materials are introduced into cells to play roles in
diagnostics (e.g., quantum dots in visualization), but also potentially as active components.
8 Nano-engineered gels and other materials are used to replace lost tissue or to provide
structure for the regeneration of natural tissue. Current applications include bone
replacement and nanostructures that help in the re-growth of nerves.

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9 Detection: The detection of a specific chemical or biological compound within a mixture
represents the basis for the operation of numerous devices, like chemical sensors, biosensors
and microarrays. As with catalysis, a detection reaction occurs at the material interface.
The rate, specificity and accuracy of this reaction can be improved using nanomaterials
rather then bulk materials in the detection area. The higher surface to volume ratio of

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nanomaterials increases the surface area available for detection with a positive effect on the
rate and on the limit of detection of the reaction. In addition, nanomaterials can be
designed to have specific surface properties (chemical or biochemical), tailored at a

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molecular level. This way, the active sites on the material surface can act as “locks” to
detect specific molecules. Scaling down using nanomaterials allows packing more
detection sites into the same device, thus allowing the detection of multiple analytes. This
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scaling-down capability, together with the high specificity of the detection sites obtainable
using nanomaterials, will allow the fabrication of super-small “multiplex detection devices”,
that is, devices that can test and detect more than one analyte at the time.
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10 The molecular building blocks of life — proteins, nucleic acids, lipids, carbohydrates, and
their non-biological mimics — are examples of materials that possess unique properties
determined by their size, folding, and patterns at the nanoscale. Biosynthesis
and bioprocessing offer fundamentally new ways to manufacture chemicals and
pharmaceutical products. Integration of biological building blocks into synthetic
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materials and devices will allow the combination of biological functions with other
desirable materials properties. Imitation of biological systems provides a major area of
research in several disciplines. For example, the active area of bio-mimetic chemistry is
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based on this approach.

11 Nanotechnology will contribute directly to advancements in agriculture in a number of
ways: (1) molecularly engineered biodegradable chemicals for nourishing plants and
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protecting against insects; (2) genetic improvement for animals and plants; (3) delivery of
genes and drugs to animals; and (4) nano-array-based technologies for DNA testing,
which, for example, will allow a scientist to know which genes are expressed in a plant
 when it is exposed to salt or drought stress. The application of nanotechnology in
agriculture has only begun to be appreciated.

1.2.4. Implication for Engineering:

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1. Nanotechnology enabled increase in computational power which will permit the
characterization of macromolecular networks in realistic environments. Such simulations
will be essential for developing biocompatible implants and for studying the drug
discovery process.

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2. Nano-engineering is leading to better fuel cells and photovoltaics, as a better alternative
energy sources into new and bigger markets.
3. Nanotech has the potential to create new ways to store and transport energy, which, in

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turn, will enable entirely new architectures for the power grid.
4. Nano-engineered catalysts can be used to better extract oil, or turn oil into fuel for cars.
5. The replacement of carbon black in tires by nanometer-scale particles of inorganic clays
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and polymers is a new technology that is leading to the production of environmentally
friendly, wear-resistant tires.
6. Significant changes in lighting technologies are expected in the next ten years.
Semiconductors used in the preparation of light emitting diodes (LEDs) for lighting
can increasingly be sculpted on nanoscale dimensions. In the United States, roughly
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20% of all electricity is consumed for lighting, including both incandescent and
fluorescent lights. In 10 to 15 years, projections indicate that such nanotechnology-
based lighting advances have the potential to reduce worldwide consumption of
energy by more than 10%, reflecting a savings of $100 billion dollars per year and a
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corresponding reduction of 200 million tons of carbon emissions.

7. The potential importance of nano-engineered drug delivery systems can be easily
understood by the apparent ability of nano-engineering to replace chemotherapy with an
injection of specially prepared nanoparticles that kill cancer cells with minimal side
effects for the patient.
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8. Mobile communications using the latest smart-phones and notebook computers have
transformed the way that business is done and personal relationships are conducted.
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9. Nanotech is also improving medical imaging with improved diagnostic imaging

techniques. Regenerative medicine is benefiting from gels that provide structure for nerve
cells to grow back after injury, including improved stents for heart patients and even
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artificial blood cells.

10. Transportation: Nanomaterials and nanoelectronics will yield lighter, faster, and safer
vehicles and more durable, reliable, and cost-effective roads, bridges, runways, pipelines,
and rail systems.
 Industry Materials/Opportunity Advantages of Nanomaterials
Aerospace Nanomaterials and nanocoatings are It has been claimed that the use of
being used for the bodies of aircraft nanomaterials can increase the
and in aerospace components. fatigue strength of aerospace
materials by as much as 300 percent.

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Nanomaterials may also be
considerably lighter, reducing the
fuel required—a critical issue in
today’s highly unprofitable airline
industry. Nanomaterials may be
especially useful for space vehicles
that must meet extreme conditions—

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especially with regard to heat.
Automotive Nanocrystalline silicon nitride and These materials demonstrate
silicon carbide have been used in impressive mechanical and chemical

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springs, ball bearings, and other properties that contribute to both the
automotive components. manufacturability and longevity of
these components.
Nanocrystalline ceramic liners for
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engine cylinders. been used to retain heat in cylinders
and improve the efficiency of
combustion.
Batteries The latest generation of batteries These nano-engineered plates can
use nano-engineered aerogels for store more energy than conventional
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separator plates. plates.
Building Aerogels for insulation and “smart The structure of aerogels makes them
materials windows” that darken when the sun excellent insulating materials.
is bright and get more transparent in
dimmer light.
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Machine Nanocrystalline metal carbide Nanocrystalline metal carbide

tools materials for cutting and drilling. materials provide harder, longer-
Nanoparticles for improved lasting materials for drills and cutting
ceramics. machinery. Conventional ceramics
can be made less brittle and easier to
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work with through the addition of

nanoparticles.
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Televisions Nanomaterials used to improve the Various zinc, cadmium, and lead
and resolution of CRTs. Carbon nanomaterials have been proposed to
monitors Nanotubes used to create CRT-like produce smaller phosphors /pixels in
field emission displays (FEDs). CRT displays and hence better
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Organic polymer-based resolution. Carbon nanotubes make

flexible displays. excellent emitters and prototypes of
FEDs have been built that combine
the visual quality of a CRT, yet may
be only one inch thick.
 Regenerative Nanoengineered gels and other Nanomaterials are constructed at the
Medicine materials are used to replace lost size level of the human cell, which
tissue or to provide structure for the means that they are incorporated
regeneration of natural tissue. better into the body than other
Current applications include bone alternatives. For example, tissues can

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replacement and nanostructures that easily bond with nanoporous bone
help in the re-growth of nerves. substitutes and nerve healing is
improved when grown around
nanostructures. Most nanomaterials
used in such applications are also
very strong, which has obvious
advantages. However, there is some

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worry that the very fact that
nanomaterials integrate well into
natural body structures may cause

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body malfunctions, or even new
diseases.

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1.3 Classifications of nanostructured materials

A reduction in the spatial dimension or confinement of particles or quasi particles in a

particular crystallographic direction within a structure generally leads to changes in physical
properties of the system in that direction. Hence one classification of nanostructured materials
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and systems essentially depends on the number of dimensions which lie within the nanometre
range.

1.3.1 Nano particles:

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 Nanoparticles are particles between 1 and 100 nanometers in size.

 They exhibit three-dimensional confinement. This structure does not permit free particle
motion in any dimension.
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 Nanoparticles may exist as amorphous or crystalline structure; ie., they may have a
random arrangement of the constituent atoms or molecules (amorphous material) or the
individual atomic or molecular units may be ordered into a regular, periodic crystalline
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structure.
 If crystalline, each nanoparticle may be either a single crystal or polycrystalline; ie., it is
composed of a number of different crystalline regions or grains of differing
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crystallographic orientations (i.e., polycrystalline) giving rise to the presence of

associated grain boundaries within the nanoparticle.

Properties of nanoparticles:
  A bulk material should have constant physical properties regardless of its size, but at the
nano-scale size-dependent properties are often observed. Thus, the properties of materials
change as their size approaches the nano-scale and as the percentage of atoms at the
surface of a material becomes significant.
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An example of the change in physical and chemical properties between gold and gold
nanoparticles:
Properties Gold (Au) Gold Nano
Color Yellow Red
Electrical
Conductive Loses conductivity at 1-3 nm

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Conductivity
Magnetism Non-magnetic Becomes magnetic at 3 nm

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Chemical
Chemically inert Explosive and catalytic
Reactivity

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Physical and chemical properties of nanoparticles that may change at the nano-scale include:

Color: Nanoparticles of yellow gold and grey silicon are red in color.
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 Melting temperature: Gold nanoparticles melt at much lower temperatures (~300 °C for 2.5 nm
size) than the gold slabs (1064 °C).
 Optical Absorption: Absorption of solar radiation is much higher in materials composed of
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nanoparticles than it is in thin films of continuous sheets of material. In both solar PV and solar
thermal applications, controlling the size, shape, and material of the particles, it is possible to
control solar absorption. Zinc oxide particles have been found to have superior UV blocking
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properties compared to its bulk substitute. This is one of the reasons why it is often used in the
preparation of sunscreen lotions, and is completely photostable.
 Chemical reactivity: Suspensions of nanoparticles are possible since the interaction of the
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particle surface with the solvent is strong enough to overcome density differences, which
otherwise usually result in a material either sinking or floating in a liquid.
 Electrical conductivity: Conductivity of bulk Gold disappears when the particle is reduced to
nano.
 Magnetism: Super-paramagnetism is a form of magnetism, which appears in
small ferromagnetic (or) ferrimagnetic nanoparticles. Ferromagnetic materials smaller than
10 nm can switch their magnetisation direction using room temperature thermal energy, thus
making them unsuitable for memory storage.

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(Super Paramagnetic materials are magnetic material with permeability several times greater
than that of ferromagnetic materials).
 Mechanical strength: Clay nanoparticles when incorporated into polymer matrices increase
reinforcement, leading to stronger plastics, verifiable by a higher glass transition temperature and
other mechanical property tests. These nanoparticles are hard, and impart their properties to the
polymer (plastic).

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Synthesis:

1. Sol-Gel method:

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The following steps involved in nanoparticle synthesis are:

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Formation of stable sol solution

• Gelation via a polycondensation or polyesterification reaction
• Gel aging into a solid mass → causes contraction of the gel network, also
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(i) phase transformations and (ii) Ostwald ripening.

• Drying of the gel to remove liquid phases can lead to fundamental changes in the
structure of the gel.
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• Dehydration at temperatures as high as 800˚C, used to remove M-OH groups for stabilizing the
gel, i.e., to protect it from rehydration.
• Densification and decomposition of the gels at high temperatures (T > 800˚ C),
i.e., to collapse the pores in the gel network and to drive out remaining organic
contaminants
 2. Thermal evaporation technique

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-Electrical heating for evaporation of bulk materials in tungsten heater into low pressure inert gas
(He, Ne, Xe)

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-Transported by convection and thermophoresis to cool environment
-Subsequent nucleation and growth
-Suitable for substances having a large vapor pressure at intermediate temperatures up to about
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-Disadvantage: the operating temperature is limited by the choice of crucible
- Evolved to flow process using tubular reactor placed in electrical furnace.
- Requires rapid temperature decrease by the free jet expansion or in a turbulent jet
- Elemental nanoparticles such as Ag, Fe, Ni, Ga, TiO2, SiO2, PbS
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1.3.2 Quantum dots:

Quantum dots are extremely small semiconductor structures, usually ranging from 2-
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10 nanometers (10-50 atoms) in diameter.

 A quantum dot is a structure that is sufficiently small in all directions that electrons
contained on it have no freedom to move in a classical sense and are forced to exhibit
quantum characteristics, occupying discrete energy states just as they would in an atom.
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Indeed, quantum dots have sometimes been referred to as artificial atoms.

 The energy band gap increases with a decrease in size of the quantum dot.
 QDs obey quantum mechanical principle of quantum confinement.
 They exhibit energy band gap that determines required wavelength of radiation
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absorption and emission spectra.

 Requisite absorption and resultant emission wavelengths dependent on dot size.
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300 nm ---------------------------------------> 700 nm

The size, shape and number of electrons can be precisely controlled.

 In some quantum dots even if one electron leaves the structure there is a significant
change leaves the structure there is a significant change in the properties.

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Synthesis: Colloidal method of QD synthesis
Colloidal semiconductor nanocrystals are synthesized from precursor compounds dissolved in
solutions, much like traditional chemical processes. The synthesis of colloidal quantum dots is

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done by using precursors, organic surfactants, and solvents. Heating the solution at high
temperature, the precursors decompose forming monomers which then nucleate and generate
nanocrystals. The temperature during the synthetic process is a critical factor in determining
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optimal conditions for the nanocrystal growth. It must be high enough to allow for rearrangement
and annealing of atoms during the synthesis process while being low enough to promote crystal
growth. The concentration of monomers is another critical factor that has to be stringently
controlled during nanocrystal growth. The growth process of nanocrystals can occur in two
different regimes, "focusing" and "defocusing". At high monomer concentrations, the critical
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size (the size where nanocrystals neither grow nor shrink) is relatively small, resulting in growth
of nearly all particles. In this regime, smaller particles grow faster than large ones (since larger
crystals need more atoms to grow than small crystals) resulting in "focusing" of the size
distribution to yield nearly monodisperse particles. The size focusing is optimal when the
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monomer concentration is kept such that the average nanocrystal size present is always slightly
larger than the critical size. Over time, the monomer concentration diminishes, the critical size
becomes larger than the average size present, and the distribution "defocuses".
There are colloidal methods to produce many different semiconductors. Typical dots are made of
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binary compounds such as lead sulfide, lead selenide, cadmium selenide,cadmium

sulfide, indium arsenide, and indium phosphide. Dots may also be made from ternary compounds
such as cadmium selenide sulfide. These quantum dots can contain as few as 100 to 100,000
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atoms within the quantum dot volume, with a diameter of 10 to 50 atoms. This corresponds to
about 2 to 10 nanometers, and at 10 nm in diameter, nearly 3 million quantum dots could be
lined up end to end and fit within the width of a human thumb.
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 Applications in Medical imaging and diagnostics:

a. QDs can be used as tool for monitoring cancerous cells and providing a means to
better understand its evolution.
 b. QDs are much efficient than other optical imaging probes such as organic dyes,
allowing them to track cell processes for longer periods of time.
c. Quantum dots using its large surface area is well suited for certain kinds of drug
delivery.

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 Quantum dot LEDs:
a. Used to produce inexpensive, industrial quality white light.
b. Produce white light by intermixing red, green and blue emitting dots homogenously
than the traditional LEDs.
c. Quantum dot LED’s are extremely energy efficient. They use only a few watts, while
a regular incandescent lamp uses 30 or more watts for the same amount of light.

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 Solar cells and photovoltaics:
A cost-effective third-generation solar cell at better power conversion efficiency is
possible by utilizing QDs compared to highly expensive traditional solar cells.

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1.3.3 Nano wires:
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Systems confined in two dimensions, or quasi-1D systems, include nanowires, nano rods,
nanofilaments and nanotubes: again these could either be amorphous, single-crystalline or
polycrystalline (with nanometre-sized grains). The term ‘nano-ropes’ is often employed to
describe bundles of nanowires or nanotubes.
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Types of Nanowires:
• Metallic - Made from Nickel,Platinum or Gold
• Semi-conducting - Comprises of Silicon, Indium phosphide or Gallium Nitride
• Insulating - Silicon Dioxide or Titanium dioxide
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• Molecular – Involves repeating organic or inorganic molecular units

Synthesis methods:

1. Electro-spinning
• Uses an electrical charge to draw very fine (typically on the micro or nanoscale) fibres
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from a liquid.
• Sufficiently high voltage is applied to a liquid droplet and the body of the liquid
becomes charged.
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• When the electrostatic repelling force overcomes the surface tension force of the
polymer solution, the liquid spills out of the spinneret and forms an extremely fine
continuous filament.
• These filaments are collected onto a rotating or stationary collector with an electrode
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where they accumulate and bond together to form nanofiber fabric.

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2. Template Base synthesis
• Use in fabrication of nanorods, nanowires, and nanotubes of polymers, metals,
semiconductors, and oxides.
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• Some porous membrane with nano-size channels(pores) are used as templates to
conduct the growing of nanowires.
• Pore size ranging from 10 nm to 100 mm can be achieved.
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Applications of Nanowires:
Nanowires are promising materials for many novel applications for their unique geometry
 and unique physical properties such as:
– electrical
– magnetic
– optical
– mechanical

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1.3.4 Ultra-thin films:

Systems confined in one dimension, or quasi-2D systems, include discs or platelets,

ultrathin films on a surface and multilayered materials; the films themselves could be
amorphous, single-crystalline or nano crystalline.

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 A solvent that contains a molecular material that when applied to a surface, chemically
aligns itself to form the strongest possible bond and appear as a film. If its thickness is in

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nanoscale, it is called as Ultra-thin film.

Properties pa
Thin films are different from bulk materials and they are:
o not fully dense
o under stress
o different defect structures from bulk
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o quasi - two dimensional (very thin films)
o strongly influenced by surface and interface effects
o This will change electrical, magnetic, optical, thermal, and mechanical properties.
Synthesis methods:
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 Spin coating or spin casting, uses a liquid precursor, or sol-gel precursor deposited onto
a smooth, flat substrate which is subsequently spun at a high velocity to centrifugally
spread the solution over the substrate. The speed at which the solution is spun and
the viscosity of the sol determine the ultimate thickness of the deposited film. Repeated
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depositions can be carried out to increase the thickness of films as desired. Thermal
treatment is often carried out in order to crystallize the amorphous spin coated film. Such
crystalline films can exhibit certain preferred orientations after crystallization on single
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crystal substrates.

 Atomic layer deposition (ALD) uses gaseous precursor to deposit conformal thin films
one layer at a time. The process is split up into two half reactions, run in sequence and
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repeated for each layer, in order to ensure total layer saturation before beginning the next
layer. Therefore, one reactant is deposited first, and then the second reactant is deposited,
during which a chemical reaction occurs on the substrate, forming the desired composition.
As a result of the stepwise, the process is slower than CVD, however it can be run at low
temperatures, unlike CVD.
 Sputtering relies on a plasma (usually a noble gas, such as argon) to knock material from a
"target" a few atoms at a time. The target can be kept at a relatively low temperature, since
the process is not one of evaporation, making this one of the most flexible deposition
techniques. It is especially useful for compounds or mixtures, where different components
would otherwise tend to evaporate at different rates. Note, sputtering's step coverage is more

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or less conformal.It is also widely used in the optical media. The manufacturing of all
formats of CD, DVD, and BD are done with the help of this technique. It is a fast technique
and also it provides a good thickness control. Presently, nitrogen and oxygen gases are also
being used in sputtering.

Applications:

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Thin film solar cells: Thin-film technologies are also being developed as a means of
substantially reducing the cost of solar cells. Thin film solar cells are cheaper to
manufacture owing to their reduced material costs, energy costs, handling costs and
capital costs. This is especially represented in the use of printed electronics (roll-to-roll)

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processes. Other thin-film technologies, that are still in an early stage of ongoing research
or with limited commercial availability, are often classified as emerging or third
generation photovoltaic cells and include, organic, dye-sensitized, and polymer solar

cells.
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cells, as well as quantum dot, copper zinc tin sulfide, nano-crystal and perovskite solar

Thin-film batteries: Thin-film printing technology is being used to apply solid-

state lithium polymers to a variety of substrates to create unique batteries for specialized
applications. Thin-film batteries can be deposited directly onto chips or chip packages in
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any shape or size. Flexible batteries can be made by printing onto plastic, thin metal foil,
or paper

Further applications are:

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• microelectronics - electrical conductors, electrical barriers, diffusion barriers . . .

• magnetic sensors - sense current (I), Magnetic flux density (B) or changes in them
• gas sensors, SAW devices
• tailored materials - layer very thin films to develop materials with new properties
• optics - anti-reflection coatings
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• corrosion protection
• wear resistance
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1.3.5 Multilayered materials:

 multilayered materials are heterostructures composed of many alternating layers that are
generally stacked in a periodic manner. An artificially multilayered material is shown
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schematically in figure below.

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 The combined thickness of two adjacent layers is called the bilayer repeat length or
bilayer period.
 The principal characteristic of multilayers is a composition modulation, that is, a periodic
chemical variation. For this reason, multilayers are often referred to as compositionally
modulated materials and the bilayer repeat length is often called the composition

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modulation wavelength. Many authors prefer to reserve the term 'compositionally
modulated materials' for multilayers composed of mutually soluble layers separated by
compositionally diffuse interfaces.
 Multilayers composed of single-crystal layers that possess the same crystal structure and

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where the interfaces are in perfect atomic registry are called superlattices.

Properties :


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Fracture: Nano films show enhanced tensile fracture strength compared to fracture
strength of micro size films. Polymer multilayered thin films composed of a high
modulus brittle layer and a low modulus ductile layer displayed synergistic
improvements in the mechanical properties. These brittle-ductile multilayers have a
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greater fracture toughness than the brittle material because crakes formed in a brittle layer
will be blunted by the adjacent ductile layers.
 Elastic properties: Multilayered materials show enhanced elastic moduli compared to
bilayer materials. Such elastic modulii are called as supermodulus effect. This variations
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in modulus is fairly associated with variations in lattice spacings which can be measured
by x-ray diffraction.
 Plastic Properties: Enhancements in the yield strength, ultimate tensile strength and
hardness of multilayered thin film materials. This hardness enhancements are due to
interface strengthening effects.
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 Damping capacity: Enhancement in the apparent damping capacity of the polycrystalline

multilayered films (Cu-Ni) deposited on fused silica substrates above certain
temperatures (300 ˚C). These enhancements may be associated with grain-boundary
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sliding or with energy dissipation mechanisms localized between the layers.

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Synthesis:

 Electrodeposition has proven to be a very successful and relatively inexpensive method

of producing high-quality compositionally modulated materials, capable of depositing
metallic, ceramic, semiconductor, and polymer multilayers [26,27]. Generally speaking,
electrodeposition methods for making multilayers can be divided into two types:
 alternately plating between two deposition potential using a single electrolyte containing
two different types of ion, or periodic transfer of the substrate from one electrolyte to
another. In addition to low cost, an attractive feature of electrodeposition is the ability to
deposit films over a large area and with a relatively large overall thicknesses (several tens
of microns or more), dimensions much greater than those generally associated with

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vacuum deposition methods. Because of these features, electrodeposition may be the
most promising approach with regard to scaling up thin-film processing methods to
produce a multilayered structural material with nanoscale individual layer thicknesses but
with a large overall thickness and in-plane area.
 Sputtering has become a very popular preparation technique for the deposition of metallic

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and ceramic multilayers. Sputtering involves the collisions of ions (usually of an inert gas
such as Ar) with the surface of a target material, leading to the ejection of target atoms
that are collected in thin-film form onto a substrate. A schematic diagram for an ion gun

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sputtering system capable of depositing multilayers. An Ar+ ion beam from the target ion
gun is used to sputter material from targets mounted on a rotating assembly. Two targets
are alternately rotated in and out of the line of the target gun ion beam, resulting in the
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deposition of a multilayered film onto a stationary substrate. The substrate ion gun is
used to sputter clean the substrate before deposition, and can also be used for ion beam
assisted deposition processes. Other sputtering systems employ schemes such as
alternately
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Applications:

 Semiconductor superlattices have important technological applications in the area of

high-speed microelectronics ie., in MODFET (modulation doped field-effect
transistors)
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 In optoelectronic applications, the superlattice photoconductor are those which apply

multilayered materials. Other examples include avalanche photodiodes, infrared
lasers, and quantum confined Stark effect optical modulators.

1.4 Length Scales involved and effect on properties: Mechanical, Electronic, Optical,
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Magnetic and Thermal properties.

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 Nanoscience is the science of objects with typical sizes of 1-100 nm. If matter is divided
into such small objects the mechanical, electric, optical, and magnetic properties can
change.
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 Simply by finely dispersing ordinary bulk materials new properties can be created: inert
materials become catalysts, insulators become conductors, or stable materials become
combustible.
  Most properties of solids are altered when their dimensions approach the nanoscale. As
an example, consider a particle of 1x1x1 nm3. This contains roughly 43 = 64 atoms. Only
8 atoms of them are in the interior, while 87% of the atoms are at the surface.
The electronic, magnetic, chemical, and mechanical properties of nanoparticles are

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therefore dominated by surface atoms.

1.4.1 Effect on Mechanical Properties:

 Elastic properties: thin films, enhances the elastic moduli by 2 to more factors when their
film length is reduced to about 2 nm. Such elastic modulii are called as supermodulus
effect. This variations in modulus is fairly associated with variations in lattice spacings

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which can be measured by x-ray diffraction.
 Damping capacity: Enhancement in the apparent damping capacity of the polycrystalline
films deposited on substrates above certain temperatures (300 ˚C). These enhancements

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may be associated with grain-boundary sliding within the nanostructured materials
 Plastic Properties: Enhancements in the yield strength, ultimate tensile strength and
hardness. This hardness enhancement is due to interface strengthening effects.
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 Wear and friction: Tribology studies conducted on nanocoatings onto steel substrates
indicated the enhanced wear resistance both to lubricated and unlubricated sliding.
 Mechanical strength : Nano-composites are materials in which inorganic particles, after
suitable compatibilization, are used to improve the mechanical strength of organic
polymers. Since nanoparticles are smaller than the wavelength of light they are invisible.
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One reason for the success of composite materials is that embedded particles can
significantly improve the mechanical strength of the matrix. This can be achieved by
mixing the nanoparticles into the organic polymer.
 Tough and hard: Nanocrystalline materials which are polycrystalline are defined as
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materials with grain sizes from a few nanometers up to 100 nm which show improved
toughness and hardness. Because polycrystalline material has large pockets of regularity
(crystal) in a “sea” of atoms that are not ordered (amorphous region).
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Fig.: Polycrystalline material

 Self-organized nano-precipitates in ultrahigh strength steels: Steels with a ultrahigh
strength above 1 GPa and good ductility above are of paramount relevance for
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light weight engineering design strategies and corresponding CO2 savings. Raabe et al.
developed a new concept for precipitation hardened ductile high strength martensitic and
austenitic-martensitic steels with even up to 1.5 GPa strength. The alloys are
characterized by a low carbon content (0.01 wt.% C) and 9-15 wt.% Mn to obtain
 different levels of austenite stability, and minor additions of Ni, Ti, and Mo (1-2 wt.%).
The latter elements are required for creating nano-precipitates during aging heat
treatment.
 Self-healing plastic nanocomposites: Plastic components break because of mechanical

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or thermal fatigue: Small cracks, large cracks, catastrophic failures. Self-healing is a way
of repairing these cracks without human intervention. Those plastics have nano-capsules
that release a healing agent when a crack forms. The agent travels to the crack through
nano-capillaries similar to blood flow to a wound. Polymerization is initiated when the
agent comes into contact with a catalyst embedded in the plastic. The chemical reaction
forms a polymer to repair the broken edges of the plastic. New bond is complete in an

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hour at room temperature.
 Strong and light weight: Carbon Nanotubes are 100 times stronger than steel but six
times lighter.

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 Usage of nanomaterials in vehicles, undergo reduction in its weight, which lead to
decrease in gasoline consumption and reduces the cost of spacecraft launching. Totally
economy of the country will increase.
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1.4.2 Effect on Electronic Properties:

There are three categories of materials based on their electrical properties: 1.

Conductors, 2. Semiconductors and 3. Insulators. The energy separation between the
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valence band and the conduction band is called Eg (band gap). The ability to fill the
conduction band with electrons and the energy of the band gap determine whether a
material is a conductor, a semiconductor or an insulator. In conducting materials like
metals the valence band and the conducting band overlap, so the value of Eg is
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negligible; thermal energy is enough to stimulate electrons to move to the conduction

band. In semiconductors, the band gap is a few eV. If an applied voltage exceeds the
band gap energy, electron jump from the valence band to the conduction band, thereby
forming electron-hole pairs called excitons. Insulators have large band gaps that require
an enourmous amount of voltage to overcome the threshold. This is why these materials
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do not conduct electricity. Quantum confinement of materials will change properties of

all these materials;
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Fig. Schematic illustration of the Eg in insulator, semiconductor and conductor
 Bandgap: Quantum confinement is responsible for the increase of energy difference
between energy states and band gap as shown in fig. below. Also, at very small

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dimensions when the energy levels are quantified, the band overlap present in metals
disappears and is actually transformed into a bandgap. This explains why some metals
become semiconductors as their size is decreased.
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 Absorption and emission in low wavelength: The increase of bandgap energy due to
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quantum confinement means that more energy will be needed in order to be absorbed by
the bandgap of the material. Higher energy means shorter wavelength (blue shift). The
same applies for the wavelength of the fluorescent light emitted from the nano-sized
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material, which will be higher, so the same blue shift will occur. This thus gives a
method of tuning the optical absorption and emission properties of a nano-sized
semiconductor over a range of wavelengths by controlling its crystallite size.
  Electrical conductivity: Some nanomaterials exhibit electrical properties that are
absolutely exceptional. Their electrical properties are related to their unique structure.
Two of these are fullerenes and carbon nanotubes. For instance, carbon nanotubes can be
conductors or semi-conductors depending on their nanostructure. Nanoparticles made of

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semiconducting materials Germanium , Silicon are not Semiconductors.

 Nanotubes are long, thin cylinders of carbon and are 100 times stronger than steel, very
flexible, and it can be either conducting or semi-conducting based on its diameter, twist
and number of walls in the nanotube.

 Negligible resistance: Supercapacitors, which are materials in which there is effectively

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no resistance and which disobey the classic Ohmś law.

 Ionization potential: Ionization potential at Nano sizes are higher than that for the bulk

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materials

 Computing power: Nanoelectronics have converted Gigantic computers to handheld

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computer devices. The very first computers were highly inefficient and took up
incredible amounts of space. But nanoelectronics have made computers to be fit in our
hand. Many handheld devices have more computing power than the earlier large
computers.

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Quantum effects in Nanoelectronics: Counting single electrons: From the development
of the first transistor in 1947, great interest has been directed towards the technological
development of semiconducting devices and the investigation of their physical properties.
A very vital field within this topic focuses on the electrical transport through low-
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dimensional structures, where the quantum confinement of charge carriers leads to the
observation of a variety of phenomena. In the aim of reaching even smaller sized and
more compact devices, semiconductor Indium Arsenide nanowires grown via Molecular
Beam Epitaxy technique are processed adding source and drain contacts and several types
of electrostatically coupled gates. The flexibility in tailoring the chemistry of nanowires
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will most likely make them the building blocks of nanosized devices.
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Figure: Scanning electron microscope image of the molecular-beam-epitaxy grown

Indium Arsenide nanowire with electrostatically coupled lateral gates.
  One reason to shrink electronic circuits and storage media in size is that integrated
circuits also become faster and consume less energy. Storage devices with a high density
can be faster accessible. This is a continuing motivation to go from micro to nano-
electronics.
 One driving force for nanoscience and –technology was the desire to miniaturize electric

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circuits and storage media. Over the past decades, the MOSFET, one standard transistor,
has continually been scaled down in size; modern integrated circuits incorporate
MOSFETs with feature sizes down to 32 nm. At the same time the size to store one bit of
information has decreased to 200 GB/sq.inch leading to bit sizes of 56 nm.

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1.4.3 Effect on Optical Properties:
 Change in color: In semiconductors, bandgap changes with particle size; bandgap is the
energy needed to promote an electron from the valence band to the conduction band. As

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particle size decreases, bandgaps increases and so wavelength of light emitted by the
particles decreases. When the bandgaps lie in the visible spectrum, a change in bandgap
with size means a change in color.
pa
Example: Gold, this readily forms nanoparticles but not easily oxidized, exhibits different
colors depending on particle size. Gold colloids have been used to color glasses since
early days of glass making. Ruby-glass contains finely dispersed gold-colloids. Silver
and copper also give attractive colors.
 Transmit information: Nanocomposites formed by transition metal clusters embedded in
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glass matrices exhibit interesting optical properties: Candidates for nonlinear integrated
optics, photonics→using photons instead of electrons to acquire, store, process and
transmit information. Glass is cheap, ease of processing, high durability, high
transparency
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 UV blocking: Large ZnO particles a. block UV light, b. scatter visible light and c. appear
white. But ZnO nanoparticles a. block UV light, b. do not scatter visible light because
the size of the particle is compared to the wavelength of visible light, and c. it appears
clear. Due to these properties nano ZnO is used in cosmetics.
 Interference: Natural nanomaterials in butterfly wings (photonic crystals within) are
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responsible for their attractive color effect. This is based on the constructive interference
of light wavelengths as they interact with the nanomaterials.
 Scattering: Nano-colloids (milk) shows scattering effect and the colors arises from the
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fact that different particle sizes scatter different wavelengths.

 Plasmons: Metal colloids (nano gold) show surface plasmons. This is a peculiar effect
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found in metal nanoparticles responsible for the vivid colors of metal colloids.
 Quantum fluorescence: Semiconductor quantum dots show quantum fluorescence. The
quantum confinement in nano-sized semiconductors leads to discrete energy levels from
which energy can be emitted (fluorescence) after it has been absorbed by the semiconductor.
1.4.4 Effect on Magnetic Properties:

 Magnetic moment: In nano-materials as large number of atoms are present in the surface,
they have low co-ordination number and hence posses local magnetic moment with in

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themselves.
 Due to large magnetic moment these nano-materials emhibits spontaneous magnetization
at smaller sizes.
 Super-paramagnetism is a form of magnetism, which appears in
small ferromagnetic (or) ferrimagnetic nanoparticles. Ferromagnetic materials smaller
than 10 nm can switch their magnetisation direction using room temperature thermal

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energy, thus making them unsuitable for memory storage.
 Ferro-magnetic and anti ferro magnetic multilayer nano-materials has GMR (Giant
Magneto Resistance) effect.

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 Magnetic nanoparticles are used in a range of applications, including ferrofluids, colour
 imaging, bioprocessing, refrigeration as well as high storage density magnetic memory
media. The large surface area to volume ratio results in a substantial proportion of atoms


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(those at the surface which have a different local environment) having a different
magnetic coupling with neighbouring atoms, leading to differing magnetic properties.

Whilst bulk ferromagnetic materials usually form multiple magnetic domains, small
magnetic nanoparticles often consist of only one domain and exhibit a phenomenon
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known as superparamagnetism. In this case the overall magnetic coercivity is then
lowered: the magnetizations of the various particles are randomly distributed due to
thermal fluctuations and only become aligned in the presence of an applied magnetic
field.
 Giant magnetoresistance (GMR) is a quantum mechanical magnetoresistance effect
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observed in nano-film structures composed of alternating ferromagnetic and non-

magnetic conductive layers. The 2007 Nobel Prize in Physics was awarded to Albert Fert
and Peter Grünberg for the discovery of GMR. It is a phenomenon also observed in
nanoscale multilayers consisting of a strong ferromagnet (e.g., Fe, Co) and a weaker
magnetic or non-magnetic buffer (e.g., Cr, Cu); it is usually employed in data storage and
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sensing. In the absence of a magnetic field the spins in alternating layers are oppositely
aligned through antiferromagnetic coupling, which gives maximum scattering from the
interlayer interface and hence a high resistance parallel to the layers. In an oriented
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external magnetic field the spins align with each other and this decreases scattering at the
interface and hence resistance of the device decreases.
 In magnetic materials such as Fe, Co, Ni, Fe3O4, etc., magnetic properties are size
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dependent. So, the coercive force (or magnetic memory) needed to reverse an internal
magnetic field within the particle is size dependent. Also, the strength of a particle’s
internal magnetic field can be size dependent.
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 Magnetic vortices: Magnetic thin-film square-or disc-shaped nanostructures with

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nanometer dimensions exhibit a magnetic vortex state: the magnetization vectors lie in
the film plane and curl around the structure centre. At the centre of the vortex, a small,
stable core exists where the magnetization points either up or down. The reversal of the
vortex core via excitation of the vortex gyration mode was discovered by time-resolved

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X-ray microscopy . This discovery of an easy core reversal mechanism did not only open
the possibility of using such systems as magnetic memories, but also initiated the
fundamental investigation of the core switching mechanism itself. They may pave the
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way to an alternative magnetic date storage technology.
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Figure: Three dimensional representation of the experimentally observed magnetic

vortex core profile

1.4.5 Effect on Thermal Properties:

1. Specific heat of Nanocrystalline materials (Cu, Ru, Pd) are higher than their bulk
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counterparts.
2. The melting point of nanoparticles decreases dramatically as the particle size gets
reduced
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3. Thermal conductivity of Nanotubes are more than twice the conductivity of diamonds.
4. Thermal management: Carbon nano tubes (CNTs) have good thermal conductivity
properties and can make excellent heat sinks. So, CNTs are used especially in outer
coverings of cell phones, other handhelds, and mobile computers.
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5. Intelligent clothing : This is clothing that contains built-in electronics, typically sensors
that respond to changing environmental conditions. There are many possibilities for types
of intelligent clothing of this kind. For example, clothing may change its thermal
properties or color in line with atmospheric temperature. There is also a special purpose
 for such intelligent clothing—one could imagine uniforms that contain sensors that warn
military, police, and security personnel when toxins and other dangers are around.

Possible Questions:
1. What is Nanoscience? (2 Marks)

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2. What is Nanotechnology?(2 Marks)
3. What is Nanometer scale? (2 Marks)
4. What are the factors responsible for change of properties of nanoscale material from
that of the bulk material? (2 Marks)
5. Write few characteristics of Nanoscale materials. (2 Marks)
6. What are the implications of Nanoscience and technology for Physics and Chemistry?

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(16 Marks)
7. What are the implications of Nanoscience and technology for Biology and
Engineering? (16 Marks)

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8. Write the classifications of nanomaterials. (2 marks)
9. What are nanoparticles? (2 ma4rks)
10. What are quantum dots? (2 ma4rks)
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11. What are nano wires? (2 ma4rks)
12. What are ultra thin films? (2 ma4rks)
13. What are multilayered materials? (2 ma4rks)
14. Explain the properties, synthesis methods and applications of Nano particles and
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Quantum dots (16 marks)
15. Explain the properties, synthesis methods and applications of Nano wires and Nano
particles. (16 marks)
16. Explain the properties, synthesis methods and applications of ultra thin films and
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multilayered materials (16 marks)

17. What are the effects of length scales of nanomaterials on Mechanical, Magnetic,
electronic, optical and thermal properties (16 marks)
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1

UNIT II PREPARATION METHODS

SYLLABUS:
Bottom-up Synthesis-Top-down Approach: Precipitation, Mechanical Milling, Colloidal

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routes, Self-assembly, Vapour phase deposition, MOCVD, Sputtering, Evaporation,
Molecular Beam Epitaxy, Atomic Layer Epitaxy, MOMBE.

2.1 Fabrication methods - Introduction

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a) Bottom-up approach and b) Top-down approach

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The bottom-up approach first forms the nanostructured building blocks such as
atoms and molecules and assembles them into larger nanostructured material. This is a
powerful approach of creating identical structures with atomic precision.
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The top-down approach involves the breaking down of large pieces of bulk
material to generate the required nanostructured material from them. Both approaches
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can be done in gas, liquid, solid state or in vacuum.

Top down processes:

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1. Milling
2. Lithographics
3. Machining
Bottom up processes:
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1. Vapor phase deposition methods

a. Chemical vapor deposition
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(i) Plasma assisted deposition process

(ii) Molecular beam epitaxy (MBE)
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(iii) Atomic Layer Epitaxy

(iv) Metal-Organic Molecular beam epitaxy (MOMBE)
` (v) Metal-Oxide Chemical Vapor Deposition (MOCVD)
2

b. Physical vapor deposition

(i). Evaporation
a. Thermal evaporation

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b. e-beam evaporation
(ii) Sputtering
a. DC sputtering
b. RF sputtering

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c. Magnetron sputtering
d. Reactive sputtering

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2. Self-assembly
3. Liquid phase processes
a. Colloidal method
b.
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Sol-gel method
c. Electro-deposition method
d. Precipitation
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2.2 PRECIPITATION
Nanoprecipitation is also called solvent displacement method. It involves the
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precipitation of a preformed polymer from an organic solution and the diffusion of

the organic solvent in the aqueous medium in the presence or absence of a surfactant.
The polymer generally (Poly Lactic acid for example), is dissolved in a water-
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miscible solvent of intermediate polarity, leading to the precipitation of

nanospheres. This phase is injected into a stirred aqueous solution containing a
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stabilizer as a surfactant. Polymer deposition on the interface between the water and
the organic solvent, caused by fast diffusion of the solvent, leads to the instantaneous
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formation of a colloidal suspension. To facilitate the formation of colloidal

polymer particles during the first step of the procedure, phase separation is performed
with a totally miscible solvent that is also a non solvent of the polymer. The solvent
3

displacement technique allows the preparation of nanocapsules when a small volume of

nontoxic oil is incorporated in the organic phase. Considering the oil-based central
cavities of the nanocapsules, high loading efficiencies are generally reported for

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lipophilic drugs when nanocapsules are prepared. The usefulness of this simple
technique is limited to water-miscible solvents, in which the diffusion rate is
enough to produce spontaneous emulsification. Then, even though some water-miscible
solvents produce a certain instability when mixed in water, spontaneous

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emulsification is not observed if the coalescence rate of the formed droplets is
sufficiently high.

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Although, acetone or dichloromethane are used to dissolve and increase the entrapment
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of drugs, the dichloromethane increases the mean particle size and is considered toxic.
This method is basically applicable to lipophilic drugs because of the miscibility of the
solvent with the aqueous phase, and it is not an efficient means to encapsulate
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water-soluble drugs. This method has been applied to various polymeric materials
such as PLGA36, PLA43, PCL44, and poly(methyl vinyl ether-comaleic anhydride)
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(PVM/MA)45,46. This technique was well adapted for the incorporation of

cyclosporin A, because entrapment efficiencies as high as 98% were obtained.
Highly loaded nanoparticulate systems based on amphiphilic h-cyclodextrins to
4

facilitate the parenteral administration of the poorly soluble antifungal drugs Bifonazole
and Clotrimazole were prepared according to the solvent displacement method.

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2.3 MECHANICAL MILLING
Mechanical alloying is a simple and useful processing technique that is now being
employed in the production of nanocrystals and/or nanoparticles from all material classes.
The powder materials are crushed mechanically in the rotating drum by the hard balls.

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This repeated deformation can cause large reductions in grain size to form nanoparticles.

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PRINCIPLE:
– The fundamental principle of size reduction in mechanical attrition devices
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lies in the energy imparted to the sample during impacts between the
milling media.
– Useful for ceramic processing and powder metallurgy industries
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OBJECTIVES of milling
- include particle size reduction (grinding);
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- amorphization; particle size growth;

- shape changing (flaking); agglomeration;
- solid-state blending (incomplete alloying);
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- modifying, changing, or altering properties of a material (density, flow

ability, or work hardening); and
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- mixing or blending of two or more materials or mixed phases.

- “mechanical alloying.” Mechanical alloying (MA) is a powder technique
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that allows production of homogeneous materials from blended elemental

powder mixtures.
5

TYPES OF MILLING
Different types of milling equipment are available for mechanical alloying and
nanoparticle formation. They differ in their capacity, efficiency of milling, and

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additional arrangements for heat transfer and particle removal.

1. SHAKER MILLING – 10-20 gm

2. PLANETARY BALL MILLING – few 100 gm

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3. ATTRITOR MILLING - 0.5 to 40 kg

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1. SHAKER MILLING
Shaker mills will mill about 10–20 g of powder at a time, and are most commonly
used for laboratory investigations and for alloy screening purposes. The common
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variety of the mill has one vial containing the sample and the grinding media, which is
secured in the clamp and swung energetically back and forth several thousand times a
minute. The back-and-forth shaking motion is combined with lateral movements of
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the ends of the vial. With each swing of the vial the milling media, typically hard,
spherical objects called “milling balls,” impact against each other and the end of the
vial, both milling and mixing at the same time. Because of the amplitude (about 5
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cm) and speed (about 1200 rpm) of the clamp motion, the ball velocities are high (on
the order of 5 m/s), and consequently the force of the ball’s impact is usually great.
Therefore, these mills can be considered a “high-energy” variety. The most recent
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design of this mill has provision for simultaneously milling the powders in two vials
to increase the throughput. This machine incorporates forced cooling to permit
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extended milling times. A variety of vial materials are available, including hardened
steel, alumina, tungsten carbide, zirconia, stainless steel, silicon nitride, agate, plastic,
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and polymethylmethacrylate. A majority of the research on the fundamental aspects of

MA has been carried out with some version of these shaker mills.
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2. PLANETARY BALL MILLING
A popular mill for conducting MA experiments is the planetary ball mill in which a
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few hundred grams of the powder can be milled at a time. The planetary ball mill owes its
name to the planet-like movement of its vials. These are arranged on a rotating support
disk, and a special drive mechanism causes them to rotate around their own axes. The
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centrifugal force produced by the vials rotating around their own axes and that produced
by the rotating support disk both act on the vial contents, consisting of material to be
ground and the grinding balls. Since the vials and the supporting disk rotate in opposite
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directions, the centrifugal forces alternately act in like and opposite directions. This
causes the grinding balls to run down the inside of the vial—the friction effect—followed
by the material being ground. Grinding balls lift off and travel freely through the inner
chamber of the vial and collide against the opposing inside wall—the impact effect.
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Even though the disk and the vial rotation speeds could not be independently controlled
in the earlier versions of this device, it is possible to do so in modern versions. In a single
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mill there can be either two or four milling stations. Recently, a single-version mill was
also developed. Grinding vials and balls are available in a variety of different materials,
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including agate, silicon nitride, sintered corundum, zirconia, chrome steel, Cr-Ni steel,
tungsten carbide, and polyamide.
7

3.ATTRITOR MILLING
A conventional ball mill
consists of a rotating horizontal drum

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half-filled
with steel balls that range from 0.318
to 0.635 cm in diameter. As the drum
rotates the balls drop on the metal

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powder that is being ground; the rate
of grinding increases with the speed

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of rotation. At high speeds, however,
the centrifugal force acting on the
steel balls exceeds the force of
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gravity, and the balls are pinned to the
wall of the drum. At this point the
grinding action stops. FIG. ATTRITOR MILL
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An attritor (a ball mill capable of generating higher energies) consists of a vertical

drum with a series of impellers inside it. Set progressively at right angles to each other,
the impellers energize the ball charge, causing powder size reduction due to the impact
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between balls; between the balls and the container wall; and between the balls, the
agitator shaft, and the impellers. Some size reduction appears to take place by
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interparticle collisions and ball sliding. A motor rotates the impellers, which in turn
agitate the steel balls in the drum.
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Attritors are the mills in which large quantities of powder (from about 0.5 to 40
kg) can be milled at a time. Attritors of different sizes and capacities are available. The
grinding tanks or containers are available in stainless steel or stainless steel coated with
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alumina, silicon carbide, silicon nitride, zirconia, rubber, or polyurethane. A variety of

grinding media are also available: glass, flint stones, stealite ceramic, mullite,
silicon carbide, silicon nitride, Sialon, alumina, zirconium silicate, zirconia, stainless

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steel, carbon steel, chrome steel, and tungsten carbide. The operation of an attritor is
simple. The powder to be milled is placed in a stationary tank with the grinding media.
The mixture is then agitated by a shaft with arms, rotating at a high speed of about 250
rpm. This causes the media to exert both shearing and impact forces on the material. The

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laboratory attritor works up to 10 times faster than conventional ball mills.
CONTAMINATION

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A major concern in the processing of nanoparticles by MA is the nature and
amount of impurities that contaminate the milled powder. Contamination can arise from
several sources, including
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• impurities in starting powders,
• vials and grinding media,
• milling atmosphere, and • control agents added to the powders.
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Particle agglomeration, where nanoparticles stick together because of attractive

forces, is also a serious issue at long milling times. Finally, contamination from milling
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media (e.g., stainless steel vials and balls) is a serious problem that has not yet been
thoroughly investigated. Despite these difficulties, MA is more widely used than ever and
continues to be applied to the formation of nanoparticles and nanocrystalline structures in
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an ever-increasing variety of metals, ceramics, and polymers.

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2.4COLLOIDAL ROUTES
The concept of fabricating nanoparticles by a simple colloidal process seems to be
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exciting. But to overcome the problem of aggregation or growth to micrometer-sized

particles, and to obtain processable particles, new concepts had to be developed. The
inorganic colloidal route is a special case of a precipitation process with nucleation and
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growth to amorphous or crystalline particles. If the concentration of the feed is low and
the pH value of the solution is in a range that surface charges are generated, colloidal
particles with diameters in the lower nanometer range are accessible. This has been

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shown for many systems in very diluted solutions.
The utilization of the colloidal state-of-the-art for the production of nanostructured
materials, however, was not a matter of detailed investigations in the field of sol–gel
chemistry. However, recent investigations including microwave and hydrothermal

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processing have been used for nanoparticle systems. One of the serious problems is the
strong aggregation during processing from sols to gels. This is shown in Fig. 1, where the

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formation of low-density aggregates is demonstrated.

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The exciting perspective, however, is that through simple precipitation processes a

wide variety of composition is available, ranging from simple oxides to chalcogenides
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or even metals. For these reasons, a precipitation route under a growth-controlling

condition has been developed. This process is based on the hypothesis that molecules
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able to interact with the particle surface are influencing nucleation and growth through
the interfacial free energy. It could be shown that the growth reaction follows rather
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simple rules. It also could be shown that by use of surface-controlling agents, very
uniform particle sizes in the nanometer range could be obtained. Various types of
component can be used as growth and size-controlling agents, e.g. complex-forming
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agents as diketones, which are very useful for oxides, other complex ligands, like amines
or chelating agents, which have shown their usefulness for metals or sulfides in the case
of chalcogenides like CdS2. It is postulated that these components control the surface

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free energy during the nucleation and growth process in a way that very uniform particle
size distributions are obtained. This can be explained by assuming that an optimal
coverage of the surface with the surface modifier exists that is specific for a given system
(leading to a free energy minimum), and that an exchange of ions or molecules between

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the particle can take place. In this case, the particle size can be tailored by the feed-to-
ligand (surface-controlling agent, SCA) ratio. Based on these considerations, a

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generalizable process has been developed for the fabrication of nanoparticles that is
shown schematically in Fig. 2 and described in detail.
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Fig 2. General scheme of a chemical route to nanoparticles

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`In this process, liquid precursors are used, which, as a rule, react with water in the
presence of H+ or OH- and a specific SCA to the corresponding precipitates. For multi-
component systems, diphasic systems, e.g. micro-emulsions, are preferred. After
precipitation, separation processes like centrifugation or filtration follow, after changing
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the zeta-potential to obtain weak and reversible aggregation. After precipitation, a

composition like Y–ZrO2 is only poorly crystallized. By employing the hydro- or solvo-
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thermal process fully crystallized nano-particles of about 10 nm in diameter are obtained.

The surface modifiers fulfill several requirements: they not only control nucleation and
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growth, they also prevent the agglomeration and they provide a desired surface chemistry
for further processing. Diketones are suitable for surface modification. The surface
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chemistry employed is basically not different from the well-known chemistry taking
place on all types of solid surface with reactive molecules.
. Nanoparticles in the range of 10 nm in diameter, however, show specific surface

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areas of several hundred square meters per gram. This means the contribution of the
surface modifiers to the chemistry of the nanoparticles is several orders of magnitude
larger than on common solid surfaces. This also means that the surface modifiers
influence the chemical nature of the nanoparticles remarkably, but, if small molecules are

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used, they do not contribute very much to the volume or the weight of these particles.
As is well known that nanoparticles are characterized by a large volume fraction

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of ‘disordered’ shell; the additional surface modification leads to a three-phased system,
consisting of a well-ordered core, a less ordered shell and an organic thin cover layer.
The coatings made from these particles show very interesting properties with respect to
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densification. The ‘construction principle’ of this type of new material is shown in Fig. 4.
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The assumption is made that the organic layer is able to reduce the particle to
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particle interaction and to allow a ‘gliding’ of one particle on the others surface. It is
expected that a denser packing than with uncoated particles is obtained. Gels or layers
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prepared from unmodified sols, in general, are porous due to the brittleness of the
structure. In addition to the surface chemistry, the surface modifiers also may be used to
tailor the surface charge of the particles. In this case, the modifiers have to be ionic, e.g.
12

by use of amino groupings. The surface charges are, for example, measured by
acoustophoretic measurement, which is a very fast analytical method monitoring the
surface charge. Since the surface charge, in general, is dependent on pH, the zeta

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potential (indicating the quantity of surface charges), as a rule, is measured as a function
of the pH.

2.5 SELF ASSEMBLY

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Molecular self-assembly is the spontaneous association of molecules under
equilibrium conditions into stable, structurally well-defined aggregates joined by non-

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covalent bonds. Molecular self-assembly is ever-present in biological systems and
underlies the formation of a wide variety of complex biological structures. Understanding
self-assembly and the associated non-covalent interactions that connect complementary
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interacting molecular surfaces in biological aggregates is a central concern in structural
biochemistry. Self-assembly is also emerging as a new strategy in chemical synthesis,
with the potential of generating non-biological structures with dimensions of 1 to 102
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nanometers. Structures in the upper part of this range of sizes are presently inaccessible
through chemical synthesis, and the ability to prepare them would open a route to
structures comparable in size (and perhaps complementary in function) to those that can
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be prepared by microlithography and other techniques of microfabrication.

The four strategies now followed in the synthesis of large molecules and
assemblies: (i) controlled formation of covalent bonds, (ii) covalent polymerization, (iii)
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self-organization, and (iv) molecular self-assembly. The fourth strategy used in

synthesis, and the one most relevant to nanostructures, is molecular self-assembly: that is,
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the spontaneous assembly of molecules into structured, stable, non-covalently joined

aggregates. Molecular self-assembly combines features of each of the preceding
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strategies to make large, structurally well-defined assemblies of atoms: (i) formation of

well-defined molecules of intermediate structural complexity through sequential covalent
synthesis; (ii) formation of large, stable structurally defined aggregates of these
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molecules through hydrogen bonds, van der Waals interactions, or other non-covalent
links; and (iii) use of multiple copies of one or several of the constituent molecules, or of
a polymer, to simplify the synthetic task. The key to this type of synthesis is to

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understand and control the non-covalent connections between molecules and to
understand and overcome the intrinsically unfavorable entropy involved in bringing many
molecules together in a single aggregate. For the final assembly to be stable and to have
well-defined shape, the non-covalent connections between molecules must collectively be

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stable. The strengths (30) of individual van der Waals interactions and hydrogen bonds
are weak (0.1 to 5 kcal/mol) relative to typical covalent bonds (40 to 100 kcal/mol) and

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comparable to thermal energies (RT = 0.6 kcal/mol at 300 K). Thus, to achieve
acceptable stability, molecules in self-assembled aggregates must be joined by many of
these weak non-covalent interactions (that is, large complementary areas of molecular
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surface in interacting pairs of molecules must be in van der Waals contact) or by multiple
hydrogen bonds, or both. Moreover, these interactions between molecules or parts of
molecules must be more favorable energetically than competing interactions with solvent
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and must be able to overwhelm the entropic advantages of disintegration of the ordered
aggregate into a disordered or dissociated state. Biology is replete with examples of
complex, nanoscale structures formed by self-assembly, and living systems have
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mastered the art of summing many weak interactions between chemical entities to make
large ones. Chemists are just beginning to learn this art.
Some principles of self-assembly: The single feature common to all of the
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biological structures is the reliance upon non-covalent self-assembly of preformed and

well-defined subassemblies to obtain the final structure, rather than the creation of a
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single, large, covalently linked structure. Biological self-assembly can thus be described
by a series of principles that are often (but not always) obeyed:
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1) Self-assembly involves association by many weak, reversible interactions to obtain a

final structure that represents a thermodynamic minimum. Incorrect structural units are
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rejected in the dynamic, equilibrium assembly. This equilibration allows high fidelity in
the process.
2) Self-assembly occurs by a modular process. The formation of stable subassemblies by

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sequential covalent processes precedes their assembly into the final structure. This
mechanism allows for efficient assembly from the preformed units [a "convergent
synthesis," in the terms of organic chemistry].
3) Only a small number of types of molecules are normally involved in modular self-

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assembly. Consequently, a limited set of binding interactions is required to cause the final
structure to form. This principle minimize the amount of information required for a

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particular structure.
4) Self-assembly often displays positive cooperativity.
5) Complementarity in molecular shape provides the foundation for the association
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between components. Shape-dependent association based on van der Waals and
hydrophobic interactions can be made more specific and stronger by hydrogen bonding
and electrostatic interactions.
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To summarize these observations, biological self-assembly requires only the
information embodied in the shape, surface properties, and deformability of a limited
number of molecular precursors. The association between these precursor molecules
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involves non-covalent interactions and generates a structure that is a thermodynamic

minimum. This aggregate of molecules is stabilized by contacts between molecular
surfaces of complementary shape; the stabilizing interactions are distributed over a large
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number of individually weak interactions, rather than concentrated in a small number of

strong covalent bonds.
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PHYSICAL VAPOR DEPOSITION

(Evaporation and Sputtering)
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In physical deposition systems the material to be deposited is transported from a

source to the wafers, both being in the same chamber. Two physical principles are used to
do so: Evaporation and sputtering.
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EVAPORATION
In evaporation, the source is placed in a small container with tapered walls, called
a crucible, and heated up to a temperature at which evaporation occurs. Various

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techniques are utilized to reach the high temperatures needed, including the induction of
high currents with Coils wound around the crucible and the bombardment of the material
surface with an electron beam (e-beam evaporators). This process is mainly used to
deposit metals, although dielectrics can also be evaporated. In a typical system, the

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crucible is located at the bottom of a vacuum chamber, whereas the wafers are placed
lining the dome-shaped ceiling of the chamber, Fig.(a). The main characteristic of this

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process is very poor step coverage, including shadow effects, as illustrated in Fig. (b). As
will be explained in subsequent sections, some micro fabrication techniques utilize these
effects to pattern the deposited layer. One way to improve the step coverage is by
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rotating and/or heating the wafers during the deposition.
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Fig. (a) Schematic representation of an electron-beam deposition system

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Fig. (b) Shadow effects observed in evaporated films. Arrows show the trajectory of the
material atoms being deposited

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SPUTTERING
Sputtering is a process whereby atoms are ejected from a solid target material due

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to bombardment of the target by energetic particles. It only happens when the kinetic
energy of the incoming particles is much higher than conventional thermal energies (≫ 1
eV).
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In sputtering, a target of
the material to be deposited is bombarded with high-energy inert ions (usually argon).
The outcome of the bombardment is that individual atoms or clusters are removed from
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the surface and ejected toward the wafer. The physical nature of this process allows its
use with virtually any existing material. Examples of interesting materials for micro
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fabrication that are frequently sputtered include metals, dielectrics, alloys (such as shape
memory alloys), and all kinds of compounds (for example, piezoelectric PZT). The inert
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ions bombarding the target are produced in DC or RF plasma. In a simple parallel-plate

system, the top electrode is the target and the wafers are placed horizontally on top of the
bottom electrode. In spite of its lower deposition rate, step coverage in sputtering is much
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better than in evaporation. Yet, the films obtained with this deposition process are non-
conformal. Figure (a) illustrates successive sputtering profiles in a trench.
Both evaporation and sputtering systems are often capable of depositing more than

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one material simultaneously or sequentially. This capability is very useful in obtaining
alloys and multilayers (e.g., multilayer magnetic recording heads are sputtered). For
certain low reactivity metals such as Au and Pt, the previous deposition of a thin layer of
another metal is needed to improve the adhesion. Ti and Cr are two frequently used

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adhesion promoters. Stress in evaporated or sputtered layers is typically tensile. The
deposition rates are much higher than most CVD techniques. However, due to stress

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accumulation and cracking, a thickness beyond 2µm is rarely deposited with these
processes. For thicker depositions a technique described in the next section is sometimes
used.
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Fig.(a) Typical cross section evolution of a trench while being filled with sputter
deposition
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Types of sputtering
DC sputtering,
Radio frequency sputtering
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Magnetron sputtering
High pressure oxygen sputtering
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Facing target sputtering

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Magnetron sputtering

Magnetron sputtering involves the creation of a plasma by the application of a

large DC potential between two parallel plates (Figure below). A static magnetic field is
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applied near a sputtering target and confines the plasma to the vicinity of the target. Ions
from the high-density plasma sputter material, predominantly in the form of neutral
atoms, from the target onto a substrate. A further benefit of the magnetic field is that it

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prevents secondary electrons produced by the target from impinging on the substrate and
causing heating or damage. The deposition rates produced by magnetrons are high
enough (1 mm/min) to be industrially viable; multiple targets can be rotated so as to
produce a multilayered coating on the substrate.

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Figure : Schematic diagram of a DC glow discharge apparatus in which gas atoms are
ionized by an electron filament and either deposit on a substrate or cause sputtering of a
target
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Figure : Schematic diagram of a magnetron sputtering that uses a magnetic field to

contain ionized gas molecules close to a sputtering target, giving large deposition rates

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Ions and their interaction with matter:
In comparison with electrons, ions are relatively heavy, negatively or positively
charged particles and various effects occur upon their interaction with matter. These
include ion backscattering (Rutherford backscattering spectrometry), the excitation of

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electrons and photons, X-ray bremsstrahlung, the displacement of atoms and sputtering,
as well as the possible implantation of ions within the surface of the material. The latter is

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extensively used for doping semiconductors.
Advantages:
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No container contamination will occur.
It is also possible to deposit alloy films which retain the composition of the parent
target material.
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Uses of Sputtering:

Sputtering is used extensively in the semiconductor industry to deposit thin films

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of various materials in integrated circuit processing.

Thin antireflection coatings on glass for optical applications.

Ideal method to deposit contact metals for thin-film transistors because of the low
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substrate temperatures used.

Low-emissivity coatings on glass, used in double-pane window assemblies. The

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coating is a multilayer containing silver and metal oxides such as zinc oxide, tin
oxide, or titanium dioxide.
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A large industry has developed around tool bit coating using sputtered nitrides,
such as titanium nitride, creating the familiar gold colored hard coat.
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Sputtering is also used as the process to deposit the metal (e.g. aluminium) layer
during the fabrication of CDs and DVDs.

Hard disk surfaces use sputtered CrOx and other sputtered materials.

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Sputtering is one of the main processes of manufacturing optical waveguides and
is another way for making efficient photovoltaic solar cells.

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Topics to be studied from the “Book”- Introduction to Nanoscience and
Nanotechnology-K.K. CHATTOPADHYAY & A.N. BANERJEE – Available in JIT

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library (or) Xerox material with me.
Vapour phase deposition, MOCVD, Evaporation, Molecular Beam Epitaxy, Atomic
Layer Epitaxy, MOMBE.
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UNIT V CHARECTERISATION TECHNIQUES
X-ray diffraction technique, Scanning Electron Microscopy - environmental techniques,
Transmission Electron Microscopy including high-resolution imaging, Surface Analysis
Techniques - AFM, SPM, STM, SNOM, ESCA, SIMS – Nano-indentation
5.1 X-ray diffraction technique – Material from the book titled “Introduction to

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Nanotechnology” – Charles P. Poole, Jr., Frank J. Owens.-PDF-“XRD” material sent thro’ mail.

5.2 Scanning Electron Microscopy - environmental techniques, 5.3 Transmission Electron

Microscopy including high-resolution imaging – Material from the book titled “ Introduction to
Nanoscience and Nanotechnology” – K.K. Chattopadhyay and A.N. Banerjee-PDF –“SEM-
TEM” material sent thro’ mail

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SPM-STM, AFM – Both notes and PDF material from the book titled “ Introduction to
Nanoscience and Nanotechnology” – K.K. Chattopadhyay and A.N. Banerjee available

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5.4 Surface Analysis Techniques

Introduction:

Why should surface be so important?

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1. The surface atoms are different from those in the bulk.
2. The surface atoms are the first to be encountered regarding the interaction with another phase.
3. It is the surface which interfaces with its environment, and the surface reactivity will
determine how well the material behavior in its intended function.
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Surfaces of materials have unique descriptive properties:
• Excess surface free energy
• Atomic / Molecular composition
• Chemical composition (reactivity)
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• Topography (vs. shape)

Surface characterization provides surface specific information about these properties.

 The chemical composition of a surface of a solid is often different from the interior of the
solid
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 One should not focus solely on this interior bulk composition because the chemical
composition of the surface layer of a solid is sometimes much more important
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SURFACE ANALYSIS TECHNIQUES:

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• Electron Spectroscopy for Chemical Analysis (ESCA / XPS)

• Secondary Ion Mass Spectroscopy (SIMS)
• Atomic force Microscopy (AFM)
 • Scanning probe microscopy (SPM)
• Scanning tunneling microscopy (STM)
• Scanning near field optical microscopy (SNOM)

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\SURFACE INFORMATION:
Property Technique(s)
Composition ESCA, SIMS,
Structure SIMS, ESCA,

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Orientation NEXAFS, FTIR, SFG
Spatial Distribution Imaging SIMS, AFM, microscopy

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Topography AFM
Thickness ESCA, AFM,

SCANNING PROBE MICROSCOPY (SPM)

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STM and AFM are two different types of scanning probe microscopies.
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STM: Scanning tunneling microscopy: A sharp tip is scanned over a conducting surface
at a very small distance above the surface. The electron current flowing between the surface and
the tip is monitored, physical and electron density maps of the surface can be generated with
high spatial resolution.
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AFM: Atomic force microscopy: Similar to STM but applicable to non-conducting

surfaces. The forces developed between the surface and the tip are monitored. A topographical
map of the surface is generated.
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 An efficient way to obtain images of the surface of a specimen is to scan the surface with
an electron beam in a raster pattern, similar to the way an electron gun scans the screen in a
television set. This is a systematic type scan. Surface information can also be obtained by a
scanning probe in which the trajectory of the electron beam is directed across the regions of
particular interest on the surface. The scanning can also be carried out by a probe tIiat monitors

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electrons that tunnel between the surface and the probe tip, or by a probe that monitors the force
exerted between the surface and the tip. We shall describe in turn the instrumentation systems
that carry out these three respective functions: the scanning transmission electron microscope
(SEM). The scanning tunneling microscope (STM), and the atomic force microscope (AFM).
Scanning tunneling microscope utilizes a wire with a very fine point. This fine point is
positively charged and acts as a probe when it is lowered to a distance of about 1om above the

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surface under study. Electrons at individual surface atoms are attracted to the positive charge of
the probe wire and jump (tunnel) up to it, thereby generating a weak electric current. The probe
wire is scanned back and forth across the surface in a raster pattern, in either a constant-height
mode, or a constant-current mode, in the arrangements sketched in Fig. 3.18. In the constant

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current mode a feedback loop maintains a constant probe height above the sample surface
profile, and the up/down probe variations are recorded. This mode of operation assumes a
constant tunneling barrier across the surface. In the constant-probe-height mode the tip is
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constantly changing its distance from the surface, and this is reflected in variations of the
recorded tunneling current as the probe scans. The feedback loop establishes the initial probe
height, and is then turned off during the scan. The scanning probe provides a mapping of the
distribution of the atoms on the surface.
The STM often employs a piezoelectric tripod scanner, and an early design of this
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scanner, built by Binning and Rohrer, is depicted in Fig. 3.19. A piezoelectric is a material in
which an applied voltage elicits a mechanical response, and the reverse. Applied voltages induce
piezo transducers to move the scanning probe (or the sample) in nanometer increments along the
x,y or z directions indicated on the arms (3) of the scanner in the figure. The initial setting is
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accomplished with the aid of a stepper motor and micrometer screws. The tunneling current,
which varies exponentially with the probe-surface atom separation, depends on the nature of the
probe tip and the composition of the sample surface. From a quantum-mechanical point of view,
the current depends on the dangling bond state of the tip apex atom and on the orbital states of
the surface atoms.
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The third technique. in wide use for nanostructure surface studies is atomic force
microscopy, and Fig.
3.20 presents a
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diagram of a typical
atomic force
microscope (AFM):
The fundamental
difference between
the STM and the
AFM is that the former monitors the electric tunneling current between the surface and the probe
tip and the latter monitors the force exerted between the surface and the probe tip. All three of
these scanning microscopes can provide information on the topographyand defect structure of a
surface .over distances close to the atomic scale. Figure 3.21 shows a 3-dimensional rendering of
an AFM image of chromium deposited on a surface of Si02. The surface was prepared by the

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laser-focused deposition of atomic chromium in the presence ofa Gaussian standing wave that
reproduced the observed regular array of peaks and valleys on the surface. When the laser-
focused chromium deposition was carried out in the presence of two plane waves displaced by
90° relative to each other, the two-dimensional arrangement AFM image shown in Fig. 3.22 was
obtained. Note that the separation between the peaks, 212.78nm, is the same in both images. The
peak heights are higher (13 nm) in the two-dimensional array (8 nm) than in the linear one.

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SCANNING NEAR-FIELD OPTICAL SPECTROSCOPY (SNOM)

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Scanning near-field optical microscopy (SNOM) enables studying a sample’s optical
properties with resolution far beyond the diffraction limit. Sample fluorescence, light emission,
transmission, scattering etc. can be mapped with the spatial resolution down to tens of

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nanometers. Two main approaches to the near-field microscopy exist: (i) aperture type SNOM
and (ii) aperture-less techniques. In the first case, a subwavelength size aperture on a scanning
tip is used as an optical probe. This is usually an opening in a metal coating of either an optical
fiber tip or of a cantilever. Spatial resolution in the aperture type SNOM is, in general,
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determined by the aperture diameter. Apertureless techniques are based on the near-field optical
phenomena as well, but do not require passing the light through an aperture.
Apertureless/Scattering SNOM, Tip Enhanced Raman/Fluorescence, STM Light
Emission and others fall into this category. SNOM techniques are widely used in nanophotonics
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(plasmonics, photonic crystals & waveguides etc.), laser technology, optical micro-devices and
material science.
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ELECTRON SPECTROSCOPY FOR CHEMICAL ANALYSIS (ESCA or XPS)

Electron spectroscopy for chemical analysis/X-ray photo-electron spectroscopy: X-ray
photons of precisely defined energy bombard the surface, electrons are emitted from the orbitals
of the component atoms enabling the measurement of electron kinetic energies and their binding
energies to determine the component atoms.

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Introduction
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-- ESCA provides unique information about chemical composition and chemical state of a
surface
-- useful for biomaterials
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-- advantages: surface sensitive (top few monolayers), wide range of solids, relatively non-
destructive
-- disadvantages: expensive, slow, poor spatial resolution, requires high vacuum

ESCA (also known as X-ray photoelectron spectroscopy, XPS) is based on the photoelectron
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effect. A high energy X-ray photon can ionize an atom, producing an ejected free electron with
kinetic energy KE: KE  h  BE
hυ = photon energy (e.g., for Al Kα, hυ = 1486.6 eV)
BE=energy necessary to remove a specific electron from an atom. BE orbital energy
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Instrumentation:

Essential components:
Sample: usually 1 cm2 , X-ray source: Al: 1486.6 eV; Mg 1256.6 eV, Electron Energy Analyzer:
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100 mm radius concentric, chemispherical analyzer; vary voltages to vary pass

energy.
Detector: electron multiplier (channeltron)
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All in ultrahigh vacuum (<10-8 Torr) (<10-11atm)

State-of-the-art small spot ESCA: 10 mm spot size.
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Analysis Capability:

provide unique signature of elements.

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Elemental Analysis: atoms have valence and core electrons: Core-level Binding energies

Quantitative analysis: measure intensities, use standards or sensitivity factor

ESCA can be used to

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(a) detect the presence of adsorbed proteins.
(b) estimate the amount of protein present
(c) resolution of one protein from another is difficult since many proteins share
chemical features. When spectra are taken as a function of take-off angle, Useful
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information can be obtained, for example, for the uniformity of an overlayer; fraction
covered; protein film thickness; and orientation of protein in the film.

Applications
-- Surface contamination
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-- Failure analysis
-- Effects of surface treatments
-- Coating, films
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-- Tribological effects
-- Depth Profiling (Ar+ sputtering)
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SECONDARY ION MASS SPECTROSCOPY (SIMS)

A beam of high energy (keV) primary ions bombards the surface, secondary atomic and
cluster ions are emitted and analysed with a mass spectrometer.
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In a SIMS analysis, the sample is bombarded with a beam of charged particles with
energies in the 1-25 keV range. These incoming particles are called primary ions. In the Mini
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SIMS, gallium ions (Ga + ) with an energy of about 6 keV are used as the primary ion beam. The
primary ions deposit energy into the surface layers. Around the impact site and to the depth of ~3
nm, many bonds are broken and there is much random displacement and movement of atoms.
This region is called the collision cascade. Collisions which result in translational energy being
directed back to the surface layer lead to ejection of material. This process is termed sputtering
of the surface.
The sputtered material is mostly ejected as neutral fragments, but ~1% is ejected in the
form of charged particles. These are known as secondary ions, and the vast majority are singly

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charged. Both positive and negative ions are emitted, and they range in size from single atoms to
very large clusters of atoms (molecular ions and fragments). Sputtered ions can leave the surface
some distance (up to ~ 5 nm) from the impact site. As a broad generalization, as this distance
increases the more likely is the desorption of the larger fragment ions since these need to have
the minimum of internal energy to prevent disintegration. © Millbrook Instruments Limited 2004
Typically, secondary ions have kinetic energies of the order of 20 eV, but different ions have
different energy distributions. In particular the molecular/cluster ions have significantly narrower

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distributions than atomic ions and they peak at slightly lower energy
Under typical SIMS conditions most of the sputtered material (>95%) emanates from the
uppermost two atomic layers, so the sampling depth can be taken to be ~1 nm. Large organic

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fragments are more likely to come predominantly from the surface monolayer, whilst the most
energetic atomic fragments may come from significantly deeper layers.
Primary ion bombardment also causes the emission of low energy electrons and these can
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be detected to provide sample visualization (topographic information) in a manner analogous to a
Scanning Electron Microscope (SEM).
The secondary mass spectrum is obtained by collecting the secondary ions and subjecting
them to mass filtration prior to detection. Three types of mass filter (or mass analyser) are used
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in SIMS - magnetic sector, quadrupole and time-of-flight; the MiniSIMS uses a quadrupole mass
filter. Since this device cannot filter ions with high kinetic energy, it requires an energy filter to
select the appropriate fraction of the secondary ion energy distribution prior to mass analysis.
Positive and negative secondary ion mass spectra are obtained in sequential experiments by
switching the polarity of the whole mass spectrometer.
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The mass filter must be capable of separating secondary ions that differ in mass by one
atomic mass unit (amu or dalton) over the whole mass range. The mass resolution or resolving
power (R) of the mass spectrometer is given by
R = m/∆m
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where m is the mass of the detected species and ∆m is the peak width. ∆m is often quoted
as the full width at half maximum peak height (fwhm) but in the case of the quadrupole it is
more useful to quote ∆mb, the full width at 10% maximum peak height i.e. the width at the base
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of the peak. In the MiniSIMS the quadrupole is set up to give ∆mb ~ 1 for all m, hence R ~ m.
The secondary ion current Is for a selected ion of mass m (or more correctly of
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mass/charge ratio m/z, where z is almost always unity in SIMS) is given by

Is(m) = Ip y α T C(m)
where Ip is the primary ion current, y is the sputter yield, α is the ionization probability, T
is the overall transmission of the energy and mass filters (i.e. the fraction of the sputtered ions of
a given mass which are actually detected), and C(m) is the concentration of the detected species
in the sputtered volume.
For a quadrupole set up as described above, T is of the order 0.1% and is approximately
inversely proportional to m. Therefore the sensitivity of the instrument decreases as higher mass

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ions are selected by the mass filter. © Millbrook Instruments Limited 2004 y is the total yield of
sputtered particles, neutral and charged, of mass m per incident primary ion; y is typically
between 1 and 20 for atomic species and it is a function of the mass and energy of the primary
ion and its angle of incidence (peaking strongly at ~ 60º to the surface normal). Under the
constant primary beam conditions in the MiniSIMS, y only varies by a factor of 5 for different
elements.

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SIMS is therefore inherently non-quantitative, i.e. there is no simple a priori relationship
between concentration of a given mass C(m) and peak intensity, Is(m). However, for a given
elemental species in a fixed matrix, and provided the concentration range is not too great, the
intensity ratio of the elemental peak to that of a matrix-related peak will usually follow a linear

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relationship with concentration. This allows composition to be determined if a suitable standard
calibration material is available. Such measurements are routine for dopant elements in
semiconductor materials (e.g. B in Si) and critical to the microelectronics industry.

NANOINDENTATION:
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Nanoindentation can be used to determine the hardness and elastic modulus of materials,
including layers and coatings <100 nm thick. Nanoscratch tests can be performed to measure lateral
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forces during the scratch process. The direct measurment of friction between fibre and matrix in fibre-
reinforced composites can also be measured by performing a push-out test.
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 Question Bank for Unit-V
1. Why is spatial resolution of STM better than AFM?
2. Describe the basic principle, working of an STM?
3. Describe in brief some nano-technological applications of STM.

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4. Describe the principle and working of AFM.
5. Describe the principle and working of SNOM.
6. Describe the principle and working of ESCA.
7. Describe the principle and working of SIMS.
8. What is nanoindentation? Explain the principle and working of it.
9. What is the difference between resolution and magnification?
10. What are the basic differences between the SEM and TEM?

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11. Describe the principle, construction and working of SEM and environmental SEM.
12. Describe the principle, construction and working of TEM.
13. Describe briefly the working principle of HETEM.

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 nanomaterials

Review
Application of Nanomaterials in Biomedical Imaging
and Cancer Therapy
Sarkar Siddique 1 and James C.L. Chow 2,3, *

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1 Department of Physics, Ryerson University, Toronto, ON M5B 2K3, Canada; sarkar.siddique@ryerson.ca
2 Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto,
ON M5G 1X6, Canada
3 Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada
* Correspondence: james.chow@rmp.uhn.ca; Tel.: +1-416-946-4501




Received: 12 August 2020; Accepted: 27 August 2020; Published: 29 August 2020


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Abstract: Nanomaterials, such as nanoparticles, nanorods, nanosphere, nanoshells, and nanostars, are
very commonly used in biomedical imaging and cancer therapy. They make excellent drug carriers,
imaging contrast agents, photothermal agents, photoacoustic agents, and radiation dose enhancers,

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among other applications. Recent advances in nanotechnology have led to the use of nanomaterials
in many areas of functional imaging, cancer therapy, and synergistic combinational platforms.
This review will systematically explore various applications of nanomaterials in biomedical imaging
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and cancer therapy. The medical imaging modalities include magnetic resonance imaging, computed
tomography, positron emission tomography, single photon emission computerized tomography,
optical imaging, ultrasound, and photoacoustic imaging. Various cancer therapeutic methods
will also be included, including photothermal therapy, photodynamic therapy, chemotherapy,
and immunotherapy. This review also covers theranostics, which use the same agent in diagnosis
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and therapy. This includes recent advances in multimodality imaging, image-guided therapy,
and combination therapy. We found that the continuous advances of synthesis and design of novel
nanomaterials will enhance the future development of medical imaging and cancer therapy. However,
more resources should be available to examine side effects and cell toxicity when using nanomaterials
in humans.
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Keywords: nanoparticles; application; biomedical imaging; cancer therapy

1. Introduction
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In the past 10 years, there have been advances in nanomaterials, such as the development of
hundreds of nanoparticles (NPs)-based probes for molecular imaging. The use of NPs has enhanced
almost all major imaging techniques, particularly magnetic resonance imaging (MRI), positron emission
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tomography (PET), and optical imaging. Some of the important milestones are the use of iron oxide
NPs in T1 weighted and/or T2 weighted MRI, the design of radioisotope chelator free (use of radioactive
metals that form a stable interaction directly with the surface or core of the NP) particles for PET,
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and the development of fluorescent NPs such as carbon dots and upconverting NPs [1]. On the other
hand, novel types of optical nanoprobes, such as persistent luminescence nanoparticles (PLNPs), are
being developed to take advantage of long lasting near-infrared (NIR) luminescence capability [2].
This allows optical imaging without constant excitation and autofluorescence [3].
The latest research and advancement in nanotechnology lead to the development of various NPs
for diagnostic and therapeutic applications. Even though clinically, the number of usages of NPs
is limited by the complex demands on their pharmacokinetic properties, nanodiagnostics improve
the understanding of important physiological principles of various diseases and treatments. On the

Nanomaterials 2020, 10, 1700; doi:10.3390/nano10091700 www.mdpi.com/journal/nanomaterials

Nanomaterials 2020, 10, 1700 2 of 40

other hand, NPs are widely used in the clinic for therapeutic purposes. Therapeutic NPs improve the
accumulation and release of pharmacologically active agents at the pathological site, which overall,
increases therapeutic efficacy and reduces the incidence and intensity of the side effects. NPs hold great
promise for integrating diagnostic and therapeutic agents into a single NP for theranostic purposes.
A good example would be monitoring biodistribution and target site accumulation, quantifying and
visualizing drug release, and longitudinally assessing therapeutic efficacy. Theranostic NPs can be
used for personalized nanomedicine-based therapies [4]. Nanoparticles’ intrinsic unique magnetic or

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optical properties make their application ideal for various imaging modalities. Nanoparticles make
excellent contrast agents due to their high sensitivity, small size, and composition. Nanoparticles are
often conjugated with suitable targeting ligands on the surface of the particles. Multifunctional NPs
can be developed by incorporating various functional materials, and this enables multimodal imaging
and therapy simultaneously, also known as theranostics [5].
Although each of the imaging and therapy modalities has improved significantly over the past
few years, there are caveats in nanomaterial application that are impeding its application. For example,

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no single molecular imaging modality can offer all the required data fully characterizing the properties of
an administered agent. Each imaging modality has a major shortcoming, such as MRI has high-resolution
but low sensitivity, optical techniques have limited tissue penetration, and radioisotope imaging

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techniques have relatively poor resolution but high sensitivity. Combining multiple imaging techniques
can enable these applications to complement one another, and a multimodal imaging agent becomes
the key to enhancing those imaging systems [6].
This review analyzed the different roles of nanomaterials, such as contrast agent and dose enhancer,
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in biomedical imaging and cancer therapy. Moreover, the review discussed the underlying mechanisms
of nanomaterials including physical, chemical, and biological mechanisms. Some new applications of
nanomaterials as theranostic agents are explored. Through a thorough understanding of the recent
advances in nanomaterial application in biomedical imaging and cancer therapy, we identified new
directions for the optimization and clinical transformation of nanomaterials.
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2. Medical Imaging
Medical imaging has improved significantly in recent decades and allows us to precisely obtain
anatomical information via different modalities. Nanoparticles play a significant part in medical
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imaging, as discussed below:

2.1. Magnetic Resonance Imaging

Magnetic resonance imaging is a noninvasive imaging technique that can provide multiparametric
and comprehensive information [7]. In 1980s, magnetic resonance imaging was introduced, and it
revolutionized modern medical imaging technology. It quickly became one of the best paraclinical
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diagnostic and monitoring tools available [8]. In 2015, an estimate of 17 million MRI examinations
were performed in the United States with the use of contrast agents. The contrast agent enhances the
image and plays an important role in MRI. An ideal contrast agent should be injected and eliminated
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from the body without any adverse effects; however, many of the current contrast agents show side
effects such as allergic reactions, nephrotoxicity, gadolinium deposition, and physiologic reactions [9].
Recent advances in NPs show their potential to be used as a contrast agent in MRI and minimize many
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of the side effects.

2.1.1. Gadolinium (Gd)

Gadolinium-based contrast agents have been used for diagnostic MRI for the last 30 years and
have continued to be studied for more functional and improved applications. Recent advances in Gd
show that when it is exposed to Zn+2 ions, they have increased r1 relaxivity [10]. This characteristic has
multiple advantages in various applications. Since Zn+2 ions are important in the biological process
involving enzyme catalyst reaction, they can be used as a biomarker for insulin secretion in β-cells.
Nanomaterials 2020, 10, 1700 3 of 40

The prostate contains a high volume of Zn+2 , which can be used to enhance the image contrast in MRI.
Collagen is dysregulated in the diseased cell or cancer cells, and excess production of collagen is seen
in common liver conditions such as alcohol and/or drug abuse. Magnetic resonance imaging can be
used to detect excess collagen with Gd NPs-based contrast agents. With increased r1 relaxivity, Gd can
covalently attach to a larger molecule, which does not involve water exchange. Multiple Gd can be
attached to a target molecule, along with enhanced permeation and retention effects, which increases
MRI contrast significantly [11]. Gadolinium can also be used as a contrast agent and carrier for IL-13

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liposome to bypass the blood–brain barrier and use the interleukin-13 receptor as a targeting moiety in
the detection of glioma [12].
Dendrimers have great potential in nanomedical imaging and MRI applications. They have very
adventitious properties such as their rigidity, low polydispersity, and ease of surface modification.
Some applications of dendrimers in MRI are cell tracking, lymph node imaging, blood pool imaging,
and tumour-targeted theranostic. Gadolinium is a paramagnetic agent with one of the highest
relaxivities due to the high rotational correlation time of the large dendrimer molecules. The relaxivity

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per Gd (III) ion of the dendrimer is enhanced up to six-fold compared to that of a single Gd (III)
chelate. Dendrimer-based Gd contrast agents provide excellent contrast on 3D time of flight MR
angiograms. Target-specific bindings of Gd dendrimer can significantly enhance cellular uptake, for

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example, a cyclic peptide specifically binds to fibrin fibronectin in conjugation with the Gd dendrimer.
In one study, Arg-Gly-Asp-Phe-Lys (mpa)(RGD) peptide complex was used as a targeting moiety in
combination with a multimodal Gd dendrimer contrast agent and gold nanoparticles (Au NPs) as
carriers. It was able to visualize alpha V beta 3-integrin overexpressing tumour cells on both computed
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tomography (CT) and MRI. Targeted dendrimers can also be used as a therapeutic agent. In neutron
capture therapy, dendrimers are irradiated with an external neutron beam; then, the dendrimer-bound
Gd generates auger electrons that are highly cytotoxic to tumour cells. This method requires a high
accumulation of Gd in the target cell and has been tested on SHIN3 ovarian carcinomas. Recently,
Gd-based dendrimers have been even further optimized and provided us with Gd-17, which is
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based on a poly-L-Lysine dendrimer scaffold, glycodendrimers, and self-assembled dendritic-like

NPs. In one study, a manganese-chelating hexametric dendrimer containing six tyrosine-derived
[Mn(EDTA)(H2 O)](-2) moieties exhibited relaxivities ranging from 8.2 to 3.8 nM−1 s−1 under 0.47 to
11.7 T, which was six-fold higher on a per molecule basis compared to a single moiety. This study also
showed in a targeted manganese dendrimer, when conjugated with antibody-specific malondialdehyde
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lysine epitopes, observed enhancement larger than 60% compared to the untargeted counterpart.
Along with MRI, manganese dendrimer can also be used as a dual-mode agent for CT-MRI [13].
Another study showed gadolinium oxide with diethylene glycol polymer and magneto liposome NPs
in Hepa 1–6 cell lines could be used as a positive MRI contrast agent and marker for cell tracking [14].
Gadolinium chelates have been used in clinical use for a long time and were primarily considered safe.
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However, recent studies showed an association between a clinically approved Gd-based contrast agent
and the development of nephrogenic systemic fibrosis [15]. A few other studies showed a Gd-based
contrast agent can potentially result in Gd deposition in human bone and brain tissue, even in the
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presence of normal renal function [16,17].

2.1.2. Super Paramagnetic Iron Oxide Nano Particles (SPIONs)

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Magnetic resonance imaging contrast agents are classified as either T1 (positive) or T2 (negative).
Radiologists primarily prefer the T1 positive contrast due to the ease of distinguishability of internal
bleeding and air tissue boundaries. Gadolinium-based contrast agents are T1 contrast agents, and even
though they provide good image enhancement, they have a small risk of adverse side effects.
Superparamagnetic iron oxide nanoparticles are a good alternative to Gd. They have a hydrodynamic
diameter ranging from 1 to 100 nm. In general, large SPIONs function as T2 contrast agents, whereas
small SPIONs function as T1 [18]. Superparamagnetic iron oxide nanoparticles are particles formed by
small crystals of iron oxide, and the coating can be made of organic compounds. Three different types
Nanomaterials 2020, 10, 1700 4 of 40

of iron oxide may make up the SPIONs core: hematite (α-Fe2 O3 ), magnetite (Fe3 O4 ), and maghemite
(γ-Fe2 O3 ). Superparamagnetic iron oxide nanoparticles can be conjugated to a variety of particles,
such as antibodies, and can also be used as a drug carrier in cancer therapy [19]. A study was
conducted to observe the efficiency and viability of SPIONs’ tracking ability of stem cells. In one study,
FereTRack Direct, a SPION was used in various stem cells. Magnetic resonance imaging was used
to monitor the homing-labelled stem cell and cytotoxicity was observed. The study results showed
that it was effective at tracking the stem cells in glioma-bearing mice [20]. Clinical translation was

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greatly increased with the improvement in the delivery system and the ability to track and monitor
injected cells. Superparamagnetic iron oxide nanoparticles can be used to label cells and can easily be
monitored using MRI [21]. Clustering SPIONs into a raspberry shape within a polymeric envelope
outputs a vastly superior image contrast. A study was conducted to observe the effect of increased
transverse relaxivity in ultra-small superparamagnetic iron oxide NPs used in MRI contrast agents.
Spherical magnetic iron oxide NPs with 12 ± 2 nm size exhibited having superior T2 relaxation rate and
high relaxivities. Due to strong relaxation properties of the NPs before and after NP administration,

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MRI analysis shows the clear distinguished signal intensity of specific organ imaging, tumour imaging,
and whole-body imaging [22]. Superparamagnetic iron oxide nanoparticles have gained considerable
attention as a T2 contrast agent due to their unique magnetic properties. However, several SPIONs

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have recently been discontinued due to a variety of reasons, such as poor contrast enhancement
when compared with Gd-based contrast agents. Gadolinium-based contrast agents still need to be
investigated thoroughly due to toxicity concerns [23].
Molecular imaging combines multidisciplinary knowledge and expertise from several disciplines
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such as medical physics, imaging technology, molecular biology, bioinformatics, and mathematics.
Molecular imaging allows the study of biochemical processes of disease without disturbing the integrity
of the living subject (noninvasive imaging). Magnetic resonance imaging is well-suited to molecular
imaging due to its inherent noninvasive properties and excellent spatial resolution. Inflammation
is a process that prepares the ground for tissue healing. Due to the involvement of inflammation
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in the pathogenesis of various human conditions including infection, ischemia, atherosclerosis,

and formation of tumour metastasis, monitoring the inflammatory process is clinically important.
Misdirected leukocytes may damage healthy tissue by inducing inflammation, where molecular
methods and markers can monitor such processes. Target inflammatory cells can be tagged with
SPIONs through the internalization of the NPs. Superparamagnetic iron oxide nanoparticles-tagged
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macrophages can invade tissues through inflammatory processes. In one study, this method was tested
on a model of inflammation in the central nervous system. Upon internalization of SPIONs, microglial
cells were detected by MRI. In tumour targeting and imaging, macromolecular antibodies with cancer
cell surface receptors are the most favoured targeting moieties for the functionalization of NPs due
to their high specificity. A well-known tumour target, human epidermal growth factor receptor
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2 (Her-2/neu receptor), was attached to poly (amino acid)-coated NPs, where approximately eight
Her-2/neu antibodies attached per particle. T2 weighted MRI confirmed that the functionalized NPs
could specifically target the Her-2/neu receptors on the cell surface. Drawbacks to antibody-targeted
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NPs are their large hydrodynamic size and poor diffusion through biological barriers. Nanoparticles
functionalized with single-chain antibody fragments (scFvs) can help to solve that problem, since
they are smaller in size and can more easily cross the biological membrane. In the case of breast
cancer, more than half of human breast cancers express receptors for luteinizing hormone-releasing
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hormone (LHRH). Nanoparticles functionalized with LHRH can selectively accumulate in primary
tumour cells and metastatic cells. Some of the tumour cells overexpress transferrin receptors (TfRs),
so Tf-SPIONs can be used for specific labelling and detection of gliosarcoma and breast carcinoma.
Folate receptors are generally overexpressed in cancerous tissues. Folate molecules as a targeting
ligand can be grafted on SPIONs with different coatings such as PEG, Dextran, and 2-carboxyethyl
phosphoric acid target-specific binding [24].
Nanomaterials 2020, 10, 1700 5 of 40

2.1.3. Carbon

Carbon-13 (13 C)
Carbon-13 (13 C) MRI is a very useful metabolic imaging technique because carbon is the backbone
for all organic molecules. It can observe a wide range of biological processes relevant to human disease.
The MRI signal of carbon-13 is very low due to its natural abundance (1.1%). However, hyperpolarization
of 13 C increases the signal significantly (more than 10,000-fold) and allows nonradioactive, real-time,

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safe, and pathway-specific investigation of dynamic metabolism and physiologic processes, which were
previously not possible in imaging. The most used hyperpolarized carbon probe is [1-13 C] pyruvate.
Its polarization reached up to 50% polarization level in current clinical polarizers and it has a long T1
relaxation (approximately 67 sec in solution at 3.0 T). Pyruvate has been used to study metabolism
in a variety of diseases such as ischemia inflammation and cancer. Pyruvate is also useful for
monitoring early anticancer therapies and study energy metabolism involving cardiovascular disease.

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It can also be used to investigate metabolic changes related to hypoxia and oxidative stress [25].
Pyruvate can be used as a tool to predict cancer progression, characterize cancer biology, and be
used as a biological marker [26]. The Warburg effect is where cancer cells exhibit elevated levels of
glycolysis and lactic acid fermentation. Hyperpolarized pyruvate can be used to quantify the flux.

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Lactate dehydrogenase-mediated conversion of pyruvate to lactate is elevated in malignant cells as a
result of the Warburg effect. The high concentration of glutathione, which correlates to the increased
reduction in 1-13 C dehydroascorbate to 1-13 C vitamin C, can be associated with malignancy, and can
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be used as a detection tool [27]. A NP-based pyruvate biosensor was developed that can detect total
pyruvate level in sera [28].

Nanodiamonds
Nanodiamond is a nontoxic substrate that can be used for drug delivery and cellular tracking
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(fluorescent marker). The Overhauser effect is a proton–electron polarization transfer technique that
can enable high contrast MRI of nanodiamond in water at room temperature and in an ultra-low
magnetic field. Magnetic resonance imaging cannot efficiently detect nanodiamond directly due to
low abundance and the small gyromagnetic ratio of spin 12 13 C nuclei, which compromise the carbon
lattice. At ultra-low magnetic field, efficient Overhauser polarization transfer between electronic and
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nuclear spins in a compatible radiofrequency is possible. Radiofrequency pulsing of the electron

paramagnetic resonance transition between MRI signals continually transfers spin polarization from the
paramagnetic centers at the surface of nanodiamond to 1 H nuclei in the surrounding water. Therefore,
the presence of nanodiamond in water produces an enhancement in the 1 H MRI signal, which can
produce images with contrast sensitivity to nanodiamond concentrations [29].
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Carbon Nanotubes
Carbon nanotubes can be synthesized single-walled or multiwalled commercially and have
diameters in the nm range and length in the µm range. Since carbon nanotubes can easily be
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internalized by living cells, they are expected to have a wide range of applications in biomedicine
such as imaging and therapy. However, carbon nanotubes are insoluble in most solvents. Therefore,
noncovalent coating of amphiphilic molecules or functionalization of various chemical groups on
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the nanotube surface are carried out to make the nanotubes soluble in biologically compatible
buffers. The unique electromagnetic property of carbon nanotubes makes them highly sensitive
in various imaging modalities such as photoacoustic molecular imaging and NIR imaging [30].
Photoacoustic imaging allows higher resolution and deeper imaging depth than optical imaging. It is
found that a single-walled carbon nanotube conjugated with cyclic ArgGly-Asp (RGD) peptides can
be used as an effective contrast agent for tumours. A preclinical study showed that eight times the
photoacoustic signal in the tumour could be acquired with mice injected with targeted nanotubes
compared to mice with nontargeted nanotubes [31]. For NIR imaging, another preclinical study
Nanomaterials 2020, 10, 1700 6 of 40

showed that single-walled carbon nanotubes with sodium cholate could be used as in vivo imaging
agents to produce high-resolution imaging with deep tissue penetration and low autofluorescence in
the NIR region beyond 1 µm [32].

Graphene
Graphene is a single layer of carbon atoms arranged in a 2D honeycomb lattice. Due to its excellent
physicochemical, surface engineering, and biological properties such as small hydrodynamic size,

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low toxicity, and biocompatibility, graphene-based nanomaterials, namely, graphene–dye conjugates,
graphene–antibody conjugates, graphene–NP composites, and graphene quantum dots can act
as an in vitro and in vivo imaging agent for molecular imaging [33]. In an in vitro and in vivo
study, carboxylated photoluminescent graphene nanodots were synthesized for photoluminescent
experiments. It was found that the nanodots could enhance the visualization of tumour in mice and
therefore, was proved to be an effective optical imaging agent for detecting cancer in deep tissue

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noninvasively [34].

2.1.4. Manganese (Mn)

Manganese-based contrast agents have good biocompatibility and ideal characteristics for MRI,

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such as the short circulation time of Mn(II) ion chelate in the T1 weighted image. Manganese oxide NPs
have negligible toxicity and good T1 weighted contrast effects. If manganese oxide NPs are retained
by the reticuloendothelial system and stored up in the liver and spleen, it will lead to Mn2+ induced
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toxicity. Pegylated bis-phosphonate dendrons are attached to the surface of the manganese oxide
NPs, which can solve the problem. This improves colloidal stability, excretion ability, and relaxation
performance. Manganese oxide NPs with a hydrodynamic diameter of 13.4 ± 1.6 nm will eventually
be discharged through the hepatobiliary pathway as feces or urinary excretion. Polyethylene glycol
coating also has a high potential to reduce toxicity with manganese oxide NPs [35].
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2.1.5. Silicon (29 Si)

Hyperpolarized silicon particles can be used in MRI applications. Large silicon particles with
an average size of 2.2 µm generally have larger polarization than NPs. However, a recent study
showed that a much smaller silicon-29 particle (APS = 55 ± 12 nm) can be hyperpolarized. For MRI
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application, a silicon-based contrast agent can be produced by incorporating transition metal ions
into a particle’s body. This contrast agent shortens the nuclear spin-lattice relaxation time (T1 ) of
the protons of nearby tissues, and ultimately, amplifies the signal in T1 weighted proton imaging.
Direct detection of the silicon signal is not possible due to its low sensitivity of 29 Si nuclei, which leads
to long acquisition times. However, this limitation can be solved via hyperpolarization. Utilizing this
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technique, the imaging window span lasts around 60–120 s, which allows rapid enzymatic reactions
and anaerobic metabolism to be studied and further be used to characterize the pathology of the tissue.
One of the advantages of using a silicon-based contrast agent is its versatility of surface chemistry;
the attachment of functional organic molecules on the surface of the particles does not significantly
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reduce any of the desired nuclear magnetic resonance properties [36].

2.1.6. Peptide
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Atherosclerosis contributes to cardiovascular disease and is the leading cause of morbidity and
mortality in the United States. Atherosclerosis is characterized as a chronic and inflammatory disease.
Early detection of unstable plaques improves treatment success rate significantly. Magnetic resonance
imaging is an important imaging modality for cases such as this, due to its ability to image and
characterize the blood vessel wall and plaque in a noninvasive manner and without any ionizing
radiation. Peptide-based NPs are useful for enhancing MRI images due to their biodegradable
properties and inherent biocompatibility. Super molecular peptide amphiphile micelles can be
Nanomaterials 2020, 10, 1700 7 of 40

used to target unstable atherosclerotic plaques displaying microthrombi. The peptide amphiphile
micelles can be functionalized using two types of amphiphilic molecules containing Gd chelator.
This target-specific NP compound enhances the image and detection probability. It can be used in dual
optical imaging-MRI [37].

2.2. Computed Tomography

Computed tomography works by making use of an x-ray source and a detector array to form

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images. It has been widely used in clinical imaging for a long time and can produce an image with
high spatial and temporal resolution. It can provide 3D anatomical information of specific tissues
and organs such as the cardiovascular track, gastrointestinal track, liver, and lung noninvasively.
One drawback to CT is that it lacks sensitivity toward contrast agents, where other modalities such as
MRI shine. However, there are still few promising contrast agents available for CT [38].

2.2.1. Gold Nanoparticles

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Gold nanoparticles have unique x-ray attenuation properties and easy surface modification.
Au NPs can be functionalized with glucosamine to be an effective contrast agent [39]. Gold nanoparticles
have a high x-ray absorption coefficient and can specifically image tumours using CT with an enhanced

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permeability and retention effect (EPR). In a breast cancer experiment, Au NPs were conjugated with
PEG chains and tumour biomarkers (human epidermal growth factor 2). They were able to provide
an enhanced image in CT due to their specific targeting ability [40]. A mesenchymal stem cell is a
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type of adult stem cell that has high potential in cellular-based regenerative therapy and is able to
treat various medical conditions such as autoimmune, neurodegenerative, and cardiovascular disease.
They can also be used to repair cartilage and bones. Their most adventitious property is being able to
migrate into different tissue, and monitoring this migration is very beneficial for studying metastases.
A study was done to observe such migration of mesenchymal cells using Au NPs as a marker, and a
micro CT was used to obtain movement information from the Au NP marker [41]. The study observed
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the comparison between porous and solid Au NPs as a contrast agent and their effect on the liver
and kidney. Porous Au NPs show brighter contrast of 45 HU, where solid AuNPs show almost half
less (26 HU). Computed tomography scans of porous Au NPs show significantly enhanced contrast
as compared to solid Au NPs [42]. A new approach to Au NP-based contrast agents for CT was
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developed, where they encapsulated biodegradable poly-di (carboxylatophenoxy) phosphazene into

gold nanospheres. They can function as a contrast agent, then, subsequently break down into harmless
by-products, and the Au NPs can be released through excretion. The CT image shows that these
contrast agents can enhance the image significantly and produce a strong contrast image [43].

2.2.2. Iodine (131 I)

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Iodine-based polymer iodine NP contrast agents were introduced for high vascular contrast and
tumour loading. They have low cost and their organic structure provides biodegradation and clearance
compared to many metal NPs. They are also very small (~20 nm) in size, which provides better
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tumour penetration compared to larger NPs. The contrast agents have long blood half-life (40 h) that
provides better tumour uptake and clearance from the liver when compared to Au NPs. The agents
also efficiently accumulate in tumours and provide high contrast vascular tumour imaging [44]. In the
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imaging of thyroid diseases and radionuclide therapy, iodine has been routinely used due to its high
affinity for thyroid and relatively long half-life (8.01 days). It also has other adventitious properties,
such as gamma emission that can be used for SPECT imaging and beta minus decay, which can be
used for therapeutic purposes. Iodine-labelled glioma targeting ligands such as chlorotoxin have high
potential in targeted SPECT imaging and radionuclide therapy of glioma. A study was carried out
to functionalize polyethylenimine (PEI)-entrapped Au NPs, which were PEGylated and combined
with targeting peptide BmK, and used in CT for targeted CT/SPECT imaging and radionuclide
therapy of glioma [45]. The regional lymph node is one of the most frequent sites of early carcinoma
Nanomaterials 2020, 10, 1700 8 of 40

metastasis. There was a study to develop a sentinel lymph node tracer consisting of iodine and
docetaxel. The results of the study showed that it can simultaneously perform sentinel lymph node
CT and locoregional chemotherapy of the draining lymphatic system [46]. In functional imaging of
tumours, simultaneous imaging of multiple contrast agents is useful due to simultaneous visualization
of multiple targets that allow observation of cancer progression and its development. Iodine and Gd
have a previous record of clinical use as image enhancing agents. A study was carried out to see the
viability of them to be used as contrast agents in both dual-energy micro CT with energy integrating

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detectors and photon-counting detector-based spectral micro CT. The experimental results showed
that the contrast agents provided enhanced images. The photon-counting detector provided a lower
background signal, a better simultaneous visualization of tumour vasculature, and an intratumoural
distribution pattern of NPs compared to dual-energy micro CT with energy integrating detectors [47].

2.2.3. Bismuth

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In a study, a hybrid cluster was synthesized using PEG 2000-DSPE. It contained hydrophobic
bismuth (Bi2 S3 ) NPs and quantum dots, and could be used as a contrast enhancer for combined
CT/fluorescence imaging. The cluster produced contrast enhancement in CT imaging of the liver and
spleen after 30 min and lasted for more than 4 h. The experimental results showed that the probe had

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good biocompatibility and did not disrupt normal organ function [48].

2.3. Positron Emission Tomography

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Positron emission tomography (PET) is a nuclear medicine imaging technique. It uses radiotracers
to produce images of radionuclide distribution. These tracers can provide information on biological
pathways via a noninvasive method [49].

2.3.1. Gold Nanoparticles

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Gold nanoparticles are commonly used in PET. Visualization of dendritic cell migration is
possible with the recent development in highly sensitive, biocompatible, and stable imaging
agents. Tracking dendritic cell migration is important in dendritic-based immunotherapy.
Novel radioiodine-124-labelled tannic acid gold core–shell NPs were introduced for dendritic cell
labelling and tracking using PET imaging. This nanoplatform had good labelling efficiency, high
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radiosensitivity, and excellent chemical stability. It also had a negligible effect on cell biological function,
including phenotype marker expression and proliferation. The experimental results showed they were
successful at tracking dendritic cell migration [50]. For early evaluation of photothermal therapy (PTT),
a study combined 18 F—FDG PET with CT, and diffusion weighted images in tumour-bearing mice
using silica gold nanoshells. The NP-treated mice exhibited inhibited tumour growth compared to
control mice. Changes in 18 F—FDG uptake and apparent diffusion coefficient correlates with tumour
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survival and it can be used for early evaluation of PTT [51]. For brain tumours, a new 124 I-labelled gold
nanostar probe using PET was introduced. The experimental results showed that it can potentially
reach sub-mm intracranial brain tumour detection, which is superior to any available noninvasive
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imaging modality [52]. Another study focused on the PEGylated crushed gold shell- radioactive
124 I-labelled gold core nanoballs for in vivo imaging application with PET. It has high stability and

sensitivity in various pH solutions. Positron emission tomography in combination with Cerenkov

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luminescent imaging showed tumour lesions at 1 h after an injection of NPs and signals remained
visible in tumour lesions up to 24 h [53].

2.3.2. Copper (64 Cu)

Copper sulfide (CuS) NPs have noncomplex chemistry, low toxicity, and small particle size,
which makes them an ideal imaging agent. Radioactive [64 Cu]CuS NPs can be used as a radiotracer for
PET and photothermal ablation therapy using near infra-red NIR laser irradiation. When [64 Cu]CuS
Nanomaterials 2020, 10, 1700 9 of 40

NPs are conjugated to RGDfK peptide through PEG linkers, they have targeting ability and significantly
higher tumour uptake (8.4 ± 1.4% injected dose/tissue). They can be used as an enhancing PET imaging
contrast agent and also be used for theranostic application [54]. A study conjugated natriuretic peptide
receptor-binding peptide (targeting entity) with a C-type atrial natriuretic factor was conducted to
produce comb 64 Cu-CANF NPs. The study showed improved biodistribution profiles and significantly
reduced accumulation in both the liver and spleen compared to the control. The study results also
demonstrated the potential for it to be a PET imaging agent to detect atherosclerosis progression [55].

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For quantitative PET imaging macrophages in tumours, pharmacokinetically optimized 64 Cu-labelled
polyglucose NPs (Macrin) were developed [56]. Single chain antibodies have high antigen specificity
and affinity, modular structure, and fast urinary clearance, which makes them ideal to be used
as targeting ligands. An antiprostate membrane antigen, scFv, has site-specific cysteine and was
evaluated in the prostate cancer xenograft model by Cu-64 PET imaging. scFv-cys was conjugated
to copolymer distearoyl phosphatidyl ethanolamine monomethoxy polyethylene glycol-maleimide
that spontaneously assemble into homogeneous multivalent lipid NPs, which enhances tumour

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accumulation. It exhibited a 2-fold increase in tumour uptake compared to scFv alone. The antiprostate
membrane antigen scFv lipid NPs exhibited a 1.6-fold increase in tumour targeting over the nontargeted
lipid NPs. This shows its potential to be used in PET as an image enhancer [57].

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2.3.3. Other Nanoparticles
Abundant inflammatory macrophages destructing tissue leads to atherosclerosis, myocardial
infarction, and heart failure. Monitoring macrophages in patients can be useful for avoiding or early
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treating many of these diseases. 18 F-Macroflor modified polyglucose NPs have high avidity for
macrophages. They have a small size and can excrete renally. Macroflor enriches cardiac and plaque
macrophages and they increase the PET signal [58]. A nanoplatform of farnesylthiosalicylate-based
copolymer consisting of a poly (oligo (ethylene glycol) methacrylate) hydrophilic block, a poly
hydrophobic block, and a poly (4-vinyl benzyl azide) middle block was introduced. The in vivo and
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vitro nanoplatform inhibits tumour growth and can also serve as a carrier for paclitaxel. It also provides
an active azide group for incorporating a PET imaging modality via a facile strategy based on metal-free
click chemistry. Its compatible properties allow it to be used for PET image-guided drug delivery [59].
The pH-sensitive pharmaceutical-grade carboxymethylcellulose-based NPs were introduced for white
blood cells to be used in PET imaging. 68 Ga3+ was used for labelling, which provides greater spatial
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resolution and patient convenience for PET over SPECT [60]. Polyphenol and poloxamer self-assembled
supramolecular NPs have multiple hydrogen bonding between tannic acid and Pluronic F-127 in
combination with hydrophobic reactions of poly (propylene oxide) chains, which can be applied in NIRF
and PET imaging. Their excess phenolic hydroxyl groups chelating positron-emitting radionuclide 89 Zr
function as PET contrast agents. They have good biocompatibility in various cell lines, and in vitro, they
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do not induce hemolysis [61]. Cerium oxide NPs have unique surface chemistry. Cerium oxide NPs
coated with 89 Zr, a clinical PET isotope, for PET imaging and in vivo biodistribution were synthesized
and showed great potential to be used in PET imaging [62].
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2.4. Single Photon Emission Computerized Tomography

Single photon emission computerized tomography is a nuclear imaging technique that uses
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gamma rays to assess biochemical changes and the level of the molecular target within a living subject.
For the past few decades, SPECT has been the nuclear imaging technique thanks to 99m Tc [63].

2.4.1. Gold Nanoparticles

Gold nanoparticles have high potential in SPECT imaging and can be used as a contrast
agent [64]. A study showed an alternative method for functionalizing Au NPs with mannose.
Technetium (99m Tc )-radiolabelled Au NPs functionalized with mannose can track and accumulate in
lymph nodes. It can be used as a SPECT contrast agent for lymphatic mapping [65].
Nanomaterials 2020, 10, 1700 10 of 40

2.4.2. Technetium (99m Tc )

For the diagnosis of metastases in early-stage cervical cancer patients, a study was carried out to
evaluate the accuracy of 99m Tc SPECT/MRI fusion for selective assessment of nonenlarged sentinel
lymph nodes (SLN). The fused datasets of the SPECT and MR images can be used to identify SLN
on the MRI with an accurate correlation to the histologic result of each SLN. The results of the study
showed that the size and absence of sharp demarcation can be used to noninvasively assess the
presence of metastasis in cervical cancer patients without enlarged lymph nodes [66]. 99m Tc can

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be used as a targeting agent in SPECT for mapping SLN. 99m Tc in conjunction with SPECT-MRI
has been used for SLN mapping in preoperative assessment of SLN metastases in the early-stage
cervical cancer in women [67]. Single photon emission computerized tomography following 2D planer
lymphoscintigraphy in conjunction with 99m Tc NP can be used for dynamic sentinel lymph node biopsy
in penile cancer patients. Single photon emission computerized tomography and 99m Tc improved the
rate of detection of true tracer acid lymph nodes and delineated their precise anatomic localization

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in drainage basins [68]. With the help of 99m Tc nanocolloid tracer, lymph drainage mapping with
SPECT/CT can be used to select patients with minimal risk of contralateral nodal failure for unilateral
elective nodal irradiation in head-and-neck squamous cell carcinoma patients [69]. Sentinel lymph
node biopsy after intertumoural injection of 99m Tc -labelled nanocolloid with imaging of scintigraphy

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and SPECT/CT in renal tumours is feasible. However, the nondetection rate is high [70].

2.5. Optical Imaging

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Noninvasive optical imaging can visualize various classes of structures involved in autophagy
at macroscopic and microscopic dynamic levels. Optical imaging is involved in fluorescence,
chemiluminescence, and Raman imaging, which can obtain noninvasive 2D or multidimensional image
data at both the macro and micro scale. Fluorescence imaging provides intuitive results, is less time
consuming, and can more easily be interpreted than other methods. That is why it is widely preferred
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by researchers and is used in biomedical imaging application [71].

2.5.1. Fluorescence
In biological study, fluorescent NPs are generally used to localize molecule or highlight processes
in living organisms or cell culture. For fluorescence imaging, the excitation and absorption wavelengths
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should be in the NIR optical window to allow good signal detection. In general, 700–750 nm excitation
and 750–800 nm emission wavelengths are found to be the optimal range [72]. Although fluorescence
has been used for a long time in biomarker analysis, immunoassays, and diagnostic imaging, it has
several shortcomings such as wavelength range, photobleaching, and fluorescence self-quenching.
Fluorescent NPs can mitigate some of the shortcomings as they often contain multiple fluorophore
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entities, which leads to increased photoluminescent emission. Their encapsulation into the particle
provides improved stability, reduced photobleaching, and reduced toxicity [73]. Fluorescence imaging
in the NIR II window using organic fluorophores has great advantages, but has a few shortcomings,
such as relatively low fluorescence quantum yield (less than 2%). There was a study to develop a
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system with organic NPs (L1013 NPs) with a high fluorescence quantum yield of 9.9%. This was able
to noninvasively visualize real-time mouse hindlimb and vessels under a very low power density
and short exposure time. It was also able to localize tumour pathology with a tumour to normal
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tissue ratio of 11.7 ± 1.3. The study results showed its great potential to be used in optical imaging
application [74]. The NIR IIb (1500–1700 nm) window is ideal for deep tissue optical imaging, but
it faces the same general NIR issues such as lack of bright and biocompatible probes. Cubic phase
(α-phase) erbium-based rare earth NPs were introduced to be used in the NIR IIb window. It was
functionalized with a cross-linked hydrophilic polymer layer that was attached to the anti-PF-L1
antibody for molecular imaging of PD-L1 in a mouse model of colon cancer. It achieved a tumour to
normal tissue signal ratio of ~40%. It had a luminescence lifetime of ~4.6 ms that enabled simultaneous
Nanomaterials 2020, 10, 1700 11 of 40

imaging of the nanocomplex. Its cross-linked functionalized layer facilitated 90% of the nanocomplex
excretion within two weeks and showed negligible toxicity in mice [75]. Indocyanine green (ICG) is
an FDA-approved dye that has been shown to exhibit NIRII fluorescence. It was used to perform
imaging tests of real-time visualization of vascular structures in hindlimb and intracranial regions
in vivo. Fluorescence spectra show strong NIR II fluorescence of liposomal ICG. In vivo results show
the enhanced performance of liposomal ICG over control for imaging of deep (>4 mm) vascular
mimicking structures. It also provided a significantly higher contrast to signal ratio for an extended

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period which allows visualization of the hindlimb and intracranial vasculature for up to 4 h post
injection [76]. In current clinical practices, the recent development of fluorescent probes is very
important for cancer diagnosis and surgery. Functionalized fluorescent probes can be used as contrast
agents. This allows for real-time visualization of the molecular edge between cancer and adjacent
normal tissue. Fluorescence-guided surgery helps the operator decide the tissue spearing margin and
generally results in a good surgical outcome. It also reduces costs. Fluorescent Au NPs conjugated with
diatriozoic acid and nucleolin targeted AS1411 ; the aptamer can be used as a molecular contrast agent

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to reveal tumour location in the CL1−5 tumour. It can also be used as an enhancer for CT due to its high
attenuation. The conjugate has good biocompatibility, high water solubility, strong x-ray attenuation,
and visible fluorescence [77]. For triple-negative breast cancer and ovarian cancer, a fluorinated

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tracer, which enables MRI (19 F MRI), shows potential for repeated imaging sessions due to the use
of nonionizing radiation. A fluorous particle is derived from the low molecular weight amphiphilic
copolymer. It self-assembles into micelles with a hydrodynamic diameter of 260 nm, and it shows
negligible toxicity. Fluorine MRI detects molecular signatures by imaging a fluorinated tracer. In vitro
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and vivo, it was capable of tracking and monitoring immune cells and cancer cells. Their systemic
administration exhibited significant uptake into triple negative breast cancer and ovarian cancer with
minimum accumulation in off-target tissue [78]. Unravelling complex neural interactions at multiple
scales in the brain is complex and often very difficult. However, optical imaging offers a solution.
A fluorescent NPs-based probe, particularly calcium-based NPs, correlate with neuronal activity and
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can be used to monitor a full array of chemicals in the brain with improved spatial temporal and
chemical resolution. This enables mapping of the neurochemical circuit with finer precision [79].
Treatment of inflammatory disorders with glucocorticoids is possible with NPs delivery, but their
delivery needs to be controlled and monitored to minimize adverse side effects. In vivo glucocorticoid
betamethasone phosphate, in conjunction with NPs and fluorescent dye DY-647, can improve the
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treatment of inflammation with simultaneous monitoring of the delivery [80].

2.5.2. Quantum Dots

Fluorescence imaging allows for visualization of real-time details at a cellular level. However,
long-term imaging is difficult due to the poor light stability of organic fluorescent dyes.
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Graphene quantum dots are a good alternative solution. They have outstanding optical properties
and unique structural features. Graphene quantum dots are loaded on the surface of NPs for example
optical magneto ferroferric oxide@polypyrrole core–shell NPs. They have longer metabolic processes
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in blood. In vivo results show they are capable of monitoring the distribution and metabolism of
NPs [81]. Mesoporous silica NPs with graphene quantum dots can simultaneously monitor real-time
localization of the doxorubicin (DOX) carrier for proper drug targeting as a fluorescent imaging
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agent. The nanoplatform shows stable suspension and excitation-dependent photoluminescence.

They also show pH and temperature-dependent release behaviour that can be utilized in theranostic
applications. Their fluorescence properties make them suitable for optical imaging with minimal
cytotoxicity [82]. Quantum dots offer superior optical characteristics compared to organic dyes.
Their potential toxicity, however, limits their application. Topical administration can reduce toxicity.
In vivo endoscopic imaging of human bladder cancer by topical administration of quantum dots
conjugated to anti-CD47 was successful and showed no indication of acute toxicity up to 7 days after
installation [83]. The molecular profile of most cancer varies greatly between patients as well as spatially
Nanomaterials 2020, 10, 1700 12 of 40

and temporally within a single tumour mass. To account for such variance, multiplexed molecular
imaging has high potential. Multiplexed molecular imaging enables multiplexed imaging of large
panels of cancer biomarkers. Polymer dots can be used in multiplexed molecular imaging and utilizes
semiconducting polymers with strong fluorescence. Studies show a 10-fold enhanced brightness of
polymer dots over commercial fluorescent dyes. Quantum dots are fluorescent semiconductor NPs that
typically contain group II-VI (e.g., CdSe and CdTe), III-V (e.g., InP and InAs), IV-VI (e.g., PbTe, PbSe),
or I-III-VI (e.g., CuInS2 ) elements. They have a narrow and symmetric emission band (~30 nm) that can

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be tuned precisely by changing the NP sizes and compositions. The broad absorption spectra and large
stokes shifts of quantum dots allow simultaneous imaging of multiple types of quantum dots with single
wavelength excitation. Quantum dots are also often coupled to a biomolecule for targeted imaging [84].
Lead sulfide quantum dots with 1100 nm emission peaks can be used in NIR fluorescence imaging of
cerebral venous thrombosis. This was tested in septic mice and the results showed it to be a useful
tool for the evaluation of the pathological state of cerebral blood vessels in septic mice [85]. A study
introduced short wavelength infrared region emissive indium arsenide quantum dots. They have

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high-resolution multicolour imaging, are readily modifiable, provide deep penetration, and have fast
acquisition speed in small-animal model. It was capable of quantifying metabolic turnover rates of
lipoproteins in several organs simultaneously. It was also able to generate detailed 3D quantitative

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flow maps of the mouse brain vasculature [86]. Carbon quantum dot (CDs) have excitation dependent
emission, high fluorescence quantum yields, photostability, and long photoluminescence decay lifetime.
These properties make them ideal to be used in imaging modalities [87]. A versatile imaging probe
with highly luminescent cadmium free CuInSe2 /ZnS core/shell quantum dots conjugated to CGKRK
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(cys-Gly-Lys-Arg-Lys) tumour-targeting peptide was developed. It had strong tumour-specific homing
property, long circulation time, excellent photostability, and minimal toxicity. It was tested on the
glioblastoma mouse model and the targeted probe distinguished tumour boundaries and positively
labels a population of diffusely infiltrating tumour cells. This shows their potential to be used in optical
imaging [88].
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2.5.3. Gold Nanoparticles

The identification and characterization of disease-related mRNA in cells are of great significance for
early diagnosis and treatment of numerous diseases. Oligonucleotide functionalized Au NPs have high
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stability, high intracellular delivery efficiency by endocytosis and high signal-to-background ratio for
mRNA detection. Spherical nucleic acid Au NPs conjugates consisting of densely packed recognition
oligonucleotides with complementary sequences to the target mRNA was studied. It was able to
detect intracellular mRNA level [89]. Ultrasmall polyaminocarboxylate-coated Au NPs, a dithiolated
derivative of diethylenetriaminepentaacetic acid, and 1,4,7,10-tetraazacyclododecan-1-glutaric
acid-4,7,10-triacetic acid functionalized by thioctic acid show potential for image-guided radiotherapy.
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The immobilization of organic Cy5-NH2 dyes onto the Au NPs adds radiosensitizer fluorescence
properties that can be used for monitoring their internalization in cancer cells for determining their
localization in cells by fluorescence microscopy. This allows for following up their accumulation in
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tumour after intravenous injection [90].

2.5.4. Persistent Luminescence NPs

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Recently, optical imaging nanoprobes are studied as contrast agents for biomedical imaging.
These nanoprobes are used to provide early detection, accurate diagnosis, and treatment monitoring at
the cellular and molecular level. One type of nanoprobes, called PLNPs, are developed as biomedical
imaging agents (bioluminescence and fluorescence imaging), because their optical property can be
varied by chemical and physical variables such as composition, size, and surface nature [2]. The PL
mechanism is that when the PL materials are irradiated by light and the materials are charged until the
excitation is stopped. Then, the PL materials emit light [91]. Preclinical studies on bioimaging were
carried out to show that PLNPs have advantages of high signal-to-noise ratio, high sensitivity, deep
Nanomaterials 2020, 10, 1700 13 of 40

penetration, and no interference from tissue autofluorescence [92,93]. For biocompatibility of PLNPs,
a study was conducted on small animals using the zinc gallate (ZGO) in vivo. Mice were injected
various amounts of ZGO from 1 to 8 mg. Toxicity was investigated after one day, one month, and half
a year after injection. It is found that only the elevated amount of ZGO (i.e., 8 mg per mouse) would
cause significant weight change in the mice, and this amount is about 5 times larger than the amount
typically used for in vivo imaging [94].

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2.6. Ultrasound
Ultrasound is a noninvasive imaging technique that can assess morphology, internal structure,
orientation, and margins of the lesion from multiple planes with a high resolution both in predominantly
fatty breast and dense glandular structures [95]. Ultrasound-guided drug delivery using nanobubbles
(NBs) has become a promising strategy in recent years. Nanobubbles are usually composed of gas
cores and stabilized shells. They can cross the capillary wall easily and have been used in many

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targeted therapies for cancer treatment, such as 5-fluorouracil loaded NBs for hepatocellular carcinoma.
Chitosan is the N-deacetylated derivative of chitin and is one of the most abundant biological materials
on earth. Chitosan NBs have gained considerable attention in cancer therapy due to their biosafety
and drug transportability. A study was conducted to synthesize DOX-loaded biocompatible chitosan

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NBs. Nanobubbles-mediated DOX uptake and apoptosis on Michigan cancer foundation-7 cells were
measured with flow cytometry and the results showed it to have excellent drug loading capability and
ultrasound enhancement [96]. A new ultrasound imaging contrast agent was introduced, where the
NBs were conjugated to poly (lactic-co-glycolic acid) and carried DOX as a cancer drug. The diameter
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of the NBs was 500 nm and the potential was −23 mV. Their multifunctionality allow it to be a
great theranostic agent as well. The enhanced ultrasonic and antitumour functions were observed in
in vivo results. The DOX-NBs had a drug loading efficiency of 78.6% and an encapsulation efficiency
of 7.4% [97]. Bypassing the brain blood–brain barrier opening is possible with focused ultrasound.
A study examined the stimulated acoustic emission of NBs at a different concentration to evaluate the
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blood–brain barrier opening under real-time acoustic feedback control across concentration. The study
results showed that the successful opening of the blood–brain barrier was reliably achievable under
real-time feedback [98]. An ultrasound-responsive phosphatidylserine-based paclitaxel liposomes
NBs conjugate that has a proapoptotic effect toward enhanced anticancer efficacy and image guidance
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was studied. In vitro results showed the conjugate had a 10-fold increase in cellular internalization
as compared to the control. The synergy between phosphatidylserine and paclitaxel (combination
index, CI < 0.1) provides significantly high tumour efficacy both in vitro and in vivo (98.3 ± 0.8%
tumour grown inhibition). The results also showed a significant reduction in tumour proliferation
index [99]. Enhancement of macromolecular permeation through layers of retina is possible with
ultrasound-responsive NBs. In one study, intracellular delivery of the antibody in the cell was
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quantified using Cy3-streptavidin with negligible toxicity. The results showed that macromolecular
internalization was achieved to a significant amount [100]. Fluorescence upconversion NPs are highly
sensitive and can function as nanocarriers. They can also label the tumour in a specific organ under
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NIR light. NIR has a few drawbacks to it, such as having a penetration depth of approximately
15 mm. Fluorescence in combination with ultrasound can overcome that shortcoming and provide a
high-resolution signal-to-noise ratio. A system in combination with Nd3+ -sensitized upconversion
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NPs, graphic carbon nanodots, and NBs were used for a dual modality imaging and treatment on a
mouse model [101]. Apatinib is an oral molecular antiangiogenetic medicine used to treat patients with
advanced hepatocellular carcinoma. It has significant systemic toxic side effects. Ultrasound-targeted
NBs destruction technology can minimize systemic drug exposure and maximize therapeutic efficacy.
A study was carried out to develop novel GPC3-targeted and drug-loaded NBs for this purpose and to
be used on hepatocellular carcinoma cells. The results showed ultrasound-targeted and drug-loaded
NBs successfully achieved the desired destruction, selective growth inhibition, and apoptosis in
HepG3 cells in vitro [102]. There was a study done to investigate the possibility of cancer therapy
Nanomaterials 2020, 10, 1700 14 of 40

using a combination of NB-liposomes and ultrasound. NB-liposome was injected intratumourally,

then, exposed to ultrasound (1 MHz, 0–4 W/cm2 , 2 min) in BALB/c mice that were inoculated with
colon-6 cells. Tumour temperature was significantly higher when treated with NB-liposome compared
to just ultrasound. It caused extensive tissue necrosis at 3–4 W/cm2 of ultrasound exposure [103].
An oxygen encapsulated cellulosic NB agent for imaging and ultrasound-guided drug delivery was
introduced. It was tested on a urothelial carcinoma model. It was propelled (max 40 mm/s) and
guided oxygen NBs to the tumour using an ultrasound beam. This can localize 500 µm inside the

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tumour using beam guidance. It enhanced the efficacy of mitomycin-C, which yielded significantly
lower tumour progression rate, while using 50% lower concentration of chemotherapeutic drug [104].
An antitumour-targeted FoxM1 siRNA-loaded cationic NBs conjugated to A10-3.2 aptamer was
introduced for prostate cancer. It has high specificity to the binding of prostate-specific membrane
antigen positive LNCaP cells. In vitro results showed it significantly improved transfection efficiency,
cell cycle arrest, and cell apoptosis, while reducing FoxM1 expression [105].

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2.7. Photoacoustic Imaging
Photoacoustic imaging (PAI) is based on the photoacoustic effect. It reconstructs images from
captured ultrasound signals generated from the materials that thermally expand by laser pulse [106].

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Photoacoustic imaging is often referred to as optoacoustic imaging. It is a low-cost modality that can
provide regional imaging of blood vessels. It has high spatial and temporal resolution with clinically
approved imaging depth [107].
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2.7.1. Gold Nanoparticles
In cancer patients, metastases rather than the primary tumour often determine tumour mortality.
A new noninvasive immune functional imaging method was proposed, where ultrasound-guided
PAI can be used to detect sentinel lymph node metastases with the aid of chitosan-coated Au NPs
(GC-Au NPs). This was tested on tumour-bearing mice. Volumetric analysis was used to quantify
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GC-Au NP accumulation in the sentinel lymph node after cellular uptake and transport by immune
cells. The analysis results showed that the spatial-temporal distribution of GC-Au NPs in the sentinel
lymph node was affected by the presence of metastases. This imaging method can successfully detect
metastatic from nonmetastatic lymph nodes using Au NPs [108]. There was a study to visualize murine
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lymph vessels using PAI and Au NPs as a contrast agent, and the study showed great potential for it
to be used to detect sentinel lymph nodes [109]. Another study found that ultrasound-guided PAI
and anti-epidermal growth factor (EGFR) antibody conjugated to gold nanorods can effectively detect
EGF-expressing primary tumour and regional lymph node metastases. The nanoconjugation was
tested on tumour-bearing mice. Anti-EGFR gold nanorods provided significant enhancement in PAI
signal in MDA-MB-231 tumour and axillary lymph node metastases relative to MCF-7 tumour and
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non-lymph node metastases [110]. Moreover, a new nanorod was synthesized through seed-mediated
synthesis with an aspect ratio ranging from 8.5 to 15.6. It could tune a longitudinal surface plasmon
resonance absorption band that covered a broad NIR range (~680–1100nm). The gold nanorods
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showed good biocompatibility and stability. The nanorods provided great contrast enhancement in PAI
(3.1 times to the control group) and excellent signal-to-noise ratio (5.6 times to the control group) [111].
When administering Au NPs as a contrast agent in PAI, it is important to note that the Au NPs are
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below the renal clearance (10 nm). A study showed that biodegradable Au NPs assembled from
5 nm primary gold particles had strong NIR absorbance. Ultra-small 5 nm Au NPs can be used to
develop molecular-activated plasmonic nanosensors for molecular-specific PAI [112]. In NIR-II tissue
generating the least background signal in PAI, large contrast agents in the spectral range delay their
pharmacokinetics and reduce their thermal stability that yields unreliable PAI. Miniaturized Au NPs
can help to solve that problem. They are 5–11 times smaller than regular gold nanorods with a similar
aspect ratio in NIR-II. They are 3 times more thermally stable and can generate 3.5 times stronger PA
signal under nanosecond pulsed laser illumination. These results were verified with thermotical and
Nanomaterials 2020, 10, 1700 15 of 40

numerical analysis [113]. Gold nanoparticles coated with glycol chitosan (GC) can be used as a contrast
agent in PAI. In breast cancer cells, GC-Au NPs have strong cellular uptake and yield a strong PA signal
in a tissue phantom. After just 3 h of incubation, the phantom displayed a strong signal and did not
require any additional antibodies or complex surface modification. The endocytosis of GC-Au NPs was
also confirmed with dark microscopy, which is beneficial for minimizing toxicity [114]. Photoacoustic
tomography (PAT) is an emerging technology that can image cells or tissue using contrast agents
such as NPs and pigments. An interesting UV–vis absorption peak in NIR was observed when Au

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NPs were synthesized with astaxanthin. Studies showed that this astaxanthin-based Au NPs had the
potential to be used in PAI and therapy [115].
In brain tumours, getting past the blood–brain barrier (BBB) is a major obstacle. The majority of
contrast agents cannot get past the BBB; thus, a study was done to use gas microbubble-assisted focused
ultrasound to transiently open the blood–brain barrier and locally deliver silica-coated gold nanorods
across the BBB. This contrast agent had strong optical absorption, which allowed for visualization of
the agent using ultrasound-guided PAI [116]. The enhancement of the amplitude of the PA signal with

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microbubbles conjugated to gold nanorods (Au MBs) was studied. Fluence below 5 mJ cm−2 provided
negligible microbubble wall motion and weak PA signal. However, fluence above 5 mJ cm−2 produced
significantly higher thermal expansion and emitted 10-fold greater amplitude PA signal compared to

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the control. This phenomenon can be explained by the idea that explosive boiling may occur at the
nanorod surface, which produces vapor NBs and contributes to Au MBs expansion. In vivo imaging
of Au MBs in a murine kidney model shows that it is an effective alternative to the existing contrast
agents for PAI [117].
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2.7.2. Carbon Nanotube (CNT)
Carbon-based NPs have gained considerable attention due to their unique physicochemical
properties in nanotechnology [118]. In one study, a single-wall CNT complex with long circulation was
fabricated. It was capable of self-assembly loading of an albumin-coupled fluorescent photosensitizer
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and Chlorin e6 via high affinity between albumin and Evans blue, which provided them with fluorescent
imaging and photodynamic ability. It was capable of providing fluorescence and PAI of tumours for
optimizing therapeutic time window [119].

2.7.3. Fluorescent
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A metabolically digestible imaging probe was developed from nanoprecipitation of biliverdin.

These NPs are composed of a biliverdin network and are cross-linked with a bifunctional amine
linker. Their excitation at NIR wavelengths provides a strong photoacoustic signal. In vivo, they
accumulated in a lymph node in mice and have the potential to be used as a photoacoustic agent for
sentinel lymph node detection [120]. The nanocomplex consists of split fluorescent protein fragment
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used as a molecular glue and switchable Raman reporters to assemble Au NPs into photonic clusters.
The fluorescent protein-driven assembly of metal colloids yields an enhanced PA signal that can
be used as PAI agent [121]. A photoacoustic contrast agent, formulated from an FDA-approved
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antimycobacterial agent, clofazimine hydrochloride NPs, for a different purpose, was introduced
to be used for prostate cancer. It had macrophage targeting ability and high contrast absorbance at
495 nm. The experimental results on transgenic adenocarcinoma of the mouse prostate model showed
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a preferential accumulation of the NPs in a cancerous prostate cell over the control. This allows PAI
and analysis of prostate cancer [122]. Photoacoustic imaging has a penetration depth of a few cm and
can generate useful endogenous contrast from melanin and oxy-/deoxyhemoglobin. ICG is a small
molecule dye with fast clearance, bleaching effects, and rapid protein binding, and it can be used for
PAI. A study was done to entrap ICG in poly (lactic-co-glycolic acid) NPs together with perfluorocarbon
using a single emulsion method. The encapsulation of ICG within NPs decreases its photobleaching
and increases the retention of signals within the cells. It can detect as little as 0.1 × 106 cells in PAI and
the nanocomplex [123]. Core–shell silica PEG NPs were developed with photothermal, photoacoustic,
Nanomaterials 2020, 10, 1700 16 of 40

and NIR optical imaging properties. They were doped with triethoxysilane-derivatized cyanine 5.5
and cyanine 7 dyes, which give them photoacoustic properties. The study results showed they have
outstanding stability and enhanced photoacoustic signal [124]. Photoswitchable hybrid probes with
thermochromic dye and absorbing NPs were introduced where temperature-sensitive light–dark states
and spectral shifts in absorption can be switched through controllable photothermal heating of doped
NPs. It provided high contrast in PEI [125]. Hypoxia is often correlated with tumour aggressiveness
and poor treatment outcome. Early diagnosis of hypoxic tumour cells has a high potential in tumour

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control. Hypoxia-activated NPs can be used to enhance the efficiency of photoacoustic intensity,
fluorescence, and chemotherapy. Hypoxia-activated NPs are inactive during blood circulation and
normal physiological conditions. They activate in the hypoxic condition when they extravasate into
the hypoxic tumour microenvironment. Azobenzene hypoxia-activated fluorescence nanoparticles
have high potential to be used in PAI [126].

3. Cancer Therapy

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Cancer therapy is the technique of inhibition or irradiation of cancer cells. There are several
techniques available and each one is more beneficial to one type of cancer treatment than
others. Nanomaterials offer significant enhancement to many of the cancer therapies and they

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are discussed below:

3.1. Photothermal Therapy

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Photothermal therapy is a hyperthermia-based cancer therapy. The goal of this therapy is to destroy
tumour tissue while avoiding excessive heating of normal tissues. Biological tissue lacks NIR-absorbing
chromophores. The use of laser wavelength in the ‘tissue optical window’ (700–1000 nm) minimizes
tissue heating, while Au NPs have strong and tunable absorption in the NIR region. Therefore, Au NPs
and NIR can be used to facilitate selective heating of tumours with NPs [127]. Gold nanoparticles with
thiol and amine groups can be functionalized with targeted antibodies or drug products. Colloidal gold
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exhibits localized plasmon surface resonance. It can absorb light at specific wavelengths, which makes
them useful for hyperthermic cancer treatment application. A gold nanoparticle’s localized plasmon
surface resonance can be changed with the modification of the particle’s shape and size, which alters
its photothermal and photoacoustic properties, allowing utilization of different wavelengths of light.
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Its nanosize allows the particle to localize in the tumour through passive distribution and excrete
through the urinary system [128]. One of the major problems with PTT is that heat distribution is often
heterogeneous throughout the tumour, which leaves part of the tumour untreated. A new idea was
proposed which uses silica gold nanoshells to deliver fractionated PTT [129]. Gold-based NPs are the
main mediator of PTT because they offer biocompatibility, efficient light to hear conversion, ability
to be tuned to absorb NIR light which penetrates tissue more deeply, a small diameter that enables
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tumour penetration, and simple gold thiol bioconjugation chemistry for the attachment of the desired
molecule. Nanoshells, nanocages, nanorods, and nanostars are the most common nanomaterials as
photothermal transducers. The majority of Au NPs have been designed to maximally absorb within
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the first NIR window, which can safely penetrate 2–3 cm of tissue [130]. A PET-based nanoplatform
was introduced to quantitatively correlate to the heat generation of plasmonic NPs with their potential
as a cancer-killing agent. Heat generation was evaluated in human tumour xenografts in mice
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using 2-deoxy-2-[F-18]-fluoro-D-glucose (18 F—FDG) PET imaging. The platform was validated by
quantifying the photothermal efficiency of the NIR silica gold nanosphere and benchmarked it against
the solid Au NPs. The results showed the heat generation of the resonant gold nanospheres (in vitro
and in vivo) performed better compared to the control. It also showed PET could reliably be used to
monitor early treatment response in PTT [131].
In PTT, the temperature of the tumour is raised above 42 degrees Celsius to destroy the cancer
cells. A light-absorbing material or photothermal agent must be introduced into the tumour to improve
the efficacy and selectivity of the energy to heat transduction. Even though gold is the most employed
Nanomaterials 2020, 10, 1700 17 of 40

agent in PTT, magnetic NPs are a good alternative. Magnetic NPs formed by iron oxide can be used
in combination with other substances or used by themselves as photothermal agents. They can be
directed to the tumour site magnetically and their distribution in tumours and other organs can be
imaged. Their molar absorption coefficient in NIR is low when they are used alone. However, this can
be mitigated by clustering of the NPs. They can also be designed to release a drug upon heat generation,
which can be beneficial for combination therapy of PTT and chemotherapy [132].
Polymer-based NP systems have been investigated to overcome some of the limitations

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associated with traditional inorganic NPs. Some of the materials that have been investigated for this
purpose include polyaniline, polypyrrole, polydopamine, and poly-(3,4-ethylene dioxythiophene):
poly(4-styrene sulfonate). They are often conjugated with ligands for targeting ability. A specific set of
requirements should be met for NPs to be an ideal candidate for PTT, such as suitable size and uniform
shape, good dispersibility in aqueous solution, respond to light in NIR range 650–950 nm to prevent
damage to surrounding healthy tissue, sufficiently photostable to ensure adequate diffusion time to
reach tumour before losing their photosensitivity, and exhibit low or no cytotoxicity in a living system.

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Current available PTT enabling agents mainly comprise metal NPs such as gold, palladium, silver,
germanium, and carbon-based NPs. Some of the polymer-based NPs systems are listed in Table 1
below [133].

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Table 1. Polymer-based nanoparticle system for PTT [133].

Polymer Configuration Testing Stage

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NPs
F-127 Conjugated NPs
Silver core, Polyaniline shell (ICG-Ag@PANI)
NPs with lanreotide and methotrexate (LT-MTX/PANI NPs)
Polyaniline In vitro and in vivo
WS core, polyaniline shell with hyaluronic acid and chlorin e6 (Ce6)
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Polyaniline and cisplastin within folate-poly (ethylene

glycol)-distearoylphosphatidylcholine (FA-PEG-DSPE), cRGD[cyclic
(Arg-GLY-Asp-D-Phe-Lys)]-PEG-DSPE, and lecithin conjugates dubbed
FA/cRGD-PNPs
Dopamine-melanin colloidal nanospheres In vitro and in vivo
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PEGylated polydopamine NPs conjugated with ICG (PDA-ICG-PEF) loaded

In vitro
with DOX
Pegylated NPs loaded with 7-ethyl-10-hydroxycamptjotheticin (SN38) In vivo
Polydopamine
DOX encapsulated with DSPE-PEG micelles coated with polydopamine In vitro and in vivo
Fe(3)O(4) core polydopamine coated nanoshell In vitro
Polydopamine coated gold nanorods In vitro
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Polydopamine coated gold/silver NPs In vitro

Base NPs In vitro and in vivo
Base NPs In vitro
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Polypyrrole Spindle-like hollow polypyrrole nanocapsules (PPy HNCs) loaded with DOX In vivo
Ppy and rapamycin loaded into liposomes conjugated with trastuzumab
In vitro
(LRPmAB)
D-A conjugated polymer (TBDOPV-DT), with 2,2-bithiophene serving as a donor
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TBDOPV-DT and thiophene-fused benzo-difuran dione-based oligo (p-phenylenevinylene) as In vitro and in vivo
an acceptor (TBDOPV-DT NPs)
PEGylated PEDOT:PSS NPs (PDOT:PSS-PEG) In vivo
PEDOT: PSS-PEG loaded with DOX, SN38, and Ce6 In vitro
PEDOT:PSS Magnetic NPs with PEDOT: PSS Cyanine7 (Cy7), and 2-deoxyglucose
In vitro and in vivo
(2-DG)-polyethylene glcol (MNP@PES-Cy7/2-DG)
Magnetic NPs with PEDOT: PSS coating In vivo
Nanomaterials 2020, 10, 1700 18 of 40

In PTT, red blood cell-coated NPs show improved efficacy with a faster decrease in tumour
volumes and a higher survival rate than bare NPs. It is speculated that red blood cell NPs inherit the
photothermal conversion effect from inner cores and the long blood retention from the red blood cell
coating. One study showed that the combination of biodegradable, natural, and nontoxic melanin NPs
extracted from living cuttlefish and red blood cell membrane have significantly higher PTT efficacy.
Au NPs encapsulated with the antitumour drug paclitaxel-coated by anti-EpCam antibodies-modified
red blood cell membranes show increased cancer-targeting ability due to anti-EpCam antibodies.

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Paclitaxel can be released when the membrane is destroyed by the heat generated from the Au NPs
under laser irradiation to yield the anticancer effect [134].

3.2. Photodynamic Therapy (PDT)

Photodynamic therapy is a form of light therapy that uses molecular oxygen, visible light,
and photosensitizers (PS) to destroy cancer cells and pathogenic bacteria. Photodynamic therapy

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is noninvasive and selectively cytotoxic to malignant cells. It causes direct tumour cell damage
by apoptosis necrosis and autophagy. The photosensitizer is distributed directly into the tumour
site or systematically via the vascular system. In the presence of molecular oxygen, light at a
specific wavelength is applied in PDT, followed by the production of reactive oxygen species (ROS),

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which results in oxidative damage of the intracellular elements within the cell. This leads to cancer cell
death. When PS targets the vascular system of the tumour, it results in hemostasis, vessel constriction,
and breakdown. This ultimately leads to a decrease in oxygen and nutrient supply to the tumour,
which eventually results in tumour cell death. Gold nanoparticles are primarily used in PDT [135].
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Porphyrins have been approved for the treatment of cancer in PDT. They have low physiological
solubility and lack of selectivity toward tumours, which is not efficient. Nanoparticles can be used
to transport porphyrins. Silica NPs (80 nm) coated with xylan–TPPOH conjugate was studied for
such purpose and showed significant phototoxic effects from post-PDT ROS generation, and stronger
cellular uptake in the human colorectal cancer cell line. They showed high anticancer efficacy [136].
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The dual specificity of PDT relies on the accumulation of PS in tumour tissue and localized light
delivery. Tetrapyrrole structures such as bacteriochlorins, porphyrins, chlorins, and phthalocyanines
with functionalization have been widely investigated in PDT. Several compounds have already received
clinical approval. Photosensitizers conjugated to antibody, proteins, peptide, and other ligands with
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specific cellular receptors are used in targeted PDT. Nanotechnology has also been widely used for
targeted delivery. Fullerene-based PS, titania photocatalysis, and the use of upconverting NPs to
increase light penetration into tissue have been studied [137]. Table 2 is a list of several nanoplatforms
for PDT and their advantages [138].

Table 2. Nanoplatforms for PDT and their advantages [138].

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Nanoparticle Platform Advantages

Passive PDT PS tumour drug
Enhanced tumour uptake and improved phototoxicity
micelles and Liposomes
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Dendrimer encapsulated NPs High loading drug

Metal oxide NPs High loading capability, biocompatibility, easy surface modification
Immuno NPs The highly specific molecule, improved drug release within the desired cell
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Quantum dots Large absorbance cross-section and size-tunable optical properties

To achieve synergistic chemiexcited photodynamic starvation therapy against tumour metastasis,

a biomimetic nanoreactor was developed. Photosensitizers on the hollow mesoporous silica NPs
were excited by chemical energy in deep metastatic tumour tissue to generate singlet oxygen,
and then, glucose oxidase catalyzed glucose into hydrogen peroxide in PDT. This blocked nutrient
supply for starvation therapy and provided hydrogen peroxide to synergistically enhance PDT [139].
Nanomaterials 2020, 10, 1700 19 of 40

Photosensitizer chlorin e6 (Ce6) and the ferroptosis inducer erastin were self-assembled into a novel
supramolecular Ce6-erastin nanodrug though bonding and π−π stacking. Ferroptosis with nanodrug
enhances anticancer actions by relieving hypoxia and promoting ROS production [140].

3.3. Chemotherapy
Chemotherapeutic agent DOX is a member of the anthracycline class. It is heavily used in
many clinical cancer therapies. It is also one of the most used chemotherapeutic drugs for the

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treatment of breast cancer. Paclitaxel is another popular chemotherapeutic agent used in breast
cancer. Other commonly used chemotherapy regimens are cisplatin, tamoxifen, trastuzumab,
and docetaxel. The efficiency of the drug increases significantly with targeted drug delivery.
Nanoparticle-based carriers are often conjugated to them for targeted delivery. Some of the NPs
that are used in chemotherapy for breast cancer are polymer-based NPs, liposomal NPs, metal-based
NPs (Au NPs, SPIONP), carbon-based NPs, mesoporous silica NPs, and protein-based NPs [141].

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Nanoparticle vehicles are currently in clinical use and some are undergoing clinical investigation for
anticancer therapies, including dendrimers, liposomes, polymeric micelles, and protein drug NPs.
There are many new NPs drug formulations in development and undergoing early and late phase
clinical trials, including several that utilize active targeting or triggered release based on environmental

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stimuli. A variety of NP formulations have been approved by the FDA and EMA for the treatment
of a wide range of cancers. Some examples are pegylated liposomal doxorubicin and liposomal
daunorubicin, which are available in the United States. Nonpegylated liposomal doxorubicin is
approved in Europe. Nab-paclitaxel is an FDA- and EMA-approved therapy using NP albumin-bound
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particles [142]. Various types of proteins and small peptides are often conjugated to the surface of
NPs to improve the selectivity of chemotherapeutic drugs. Serum glycoprotein is one of the targeting
ligands used with NPs in chemotherapy drug delivery [143]. The antimalarial agent chloroquine can
reduce the immunological clearance of NPs by resident macrophages in the liver, leading to increased
tumour accumulation of the nanodrug [144].
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Gold nanoparticles have high stability, surface area-to-volume ratio, surface plasmon resonance,
and multifunctionalities. The nontoxic, nonimmunogenic nature, high permeability, and retention
effect of Au NPs provide additional benefits by enabling penetration and accumulation of the drug at
tumour sites. DOX-BLM-PEG-Au NPs and EpCAM-RPAnN are two Au NP carriers that have high
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potential to be used in chemotherapy [145]. Cisplatin is a genotoxic agent that can be used alone or
in combination with radiation or other chemotherapeutic agents. It is used in chemotherapy for a
broad range of cancers. However, the agent is limited by the intrinsic and acquired resistance, and the
dose to normal tissue. It shows little selectivity for tumour vs. normal tissue, which leads to toxicity.
Nanoparticles can be used to deliver cisplatin to reduce toxicity. Some organic NPs that can be used to
transport cisplatin are liposomes, polymeric NPs, polymeric micelles, and dendrimers. Some inorganic
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NPs are Au NPs, ferromagnetic NPs, and mesoporous silica NPs. Some hybrid NPs are CNT, nanoscale
coordination polymers, and polysilsesquioxane NPs [146].
Organic NPs are a popular choice for chemotherapeutic drug delivery. They can increase the
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circulation half-life and tumour accumulation of a drug. Combination chemotherapy is used in the
treatment of a broad range of cancers. Nanoparticles are essential to delivering many of these drugs to
the target site and also provide a theranostic platform for multifunction [147]. Multidrug-loaded NPs
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formulation consists of different classes of therapeutic agents. It has been studied for breast cancer
therapy in preclinical breast cancer models. One example would be polymer lipid hybrid NPs for
coencapsulated DOX and mitomycin C. It has demonstrated its efficacy in the human breast cancer
model, including multidrug resistance cells. Multidrug-loaded NPs micellar formulation was also
developed for the delivery of three drugs: paclitaxel, 17-AAG (Triolimus), and rapamycin. They were
evaluated on MDA-MB-231 tumour-bearing mice [148]. Hypoxia promotes the invasiveness of tumour
cells and chemoresistance. Tumour-associated macrophages (TAMs) reside in the hypoxic region
to promote proliferation and chemoresistance. Nanoparticles MnO2 with high reactivity toward
Nanomaterials 2020, 10, 1700 20 of 40

hydrogen peroxide for the simultaneous production of O2 and regulation of pH can affectively alleviate
tumour hypoxia by targeted delivery of MnO2 to the hypoxic area. It was conjugated to DOX and
significantly increased the apparent diffusion coefficient value of breast cancer and inhibited tumour
growth [149]. A novel carrier, targeting nanomicelles for synchronous delivery of curcumin and
baicalin, was introduced, which could effectively overcome tumour resistance. Mannose binds to
CD206 receptors on the surface of tumour-associated macrophages, subsequently increasing the
number of nanodandelions engulfed by tumour-associated macrophages. To increase tumour cellular

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uptake, oligomeric hyaluronic acid can also be used as a targeting material. Nanodandelions can easily
enter tumour tissue through the vascular barrier due to their small size. Effective antitumour activity
and reduced side effects were confirmed in antitumour experiments in A549 tumour-bearing mice [150].
Sustained-release characteristics of NPs may aid the effectiveness of chemotherapy by maintaining
drug concentrations at the tumour site for longer durations. Nanoparticles can increase penetration
and accumulation of the inhaled drug in tumour tissue and cells. This yield improved antitumour
activity compared to the free drug. These characteristics make them suitable for chemotherapy for

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lung cancer [151].

3.4. Immunotherapy

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During recent decades, cancer immune therapy has made significant progress with the
improvement in nanotechnology. Immunotherapy is a therapy based on stimulation or activation
of the patient’s immune system to recognize and destroy cancer cells [152]. Understanding how to
increase the response rate to various classes of immunotherapy is to improving cancer treatment
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efficacy and minimizing adverse side effects. There are five classes of cancer immunotherapy:
lymphocyte-promoting cytokines, agonistic antibodies against co-stimulatory receptors, checkpoint
inhibitors, engineered T cells such as CAR T and T cell receptor (TCR) T cells, and cancer vaccines.
Nanoparticles can be used to target T cells in the blood or transport mRNA to the cancer cell, or transport
other vaccines in immunotherapy [153]. Nanoparticle systems have shown to be a promising tool for
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effective antigen delivery. The antigen is generally in peptide form that can stimulate an adaptive
immune response. For conditioning a robust and long-lasting adaptive immune response, stimulation
of the innate immune system through natural killer cells is necessary. Therefore, an adjuvant that
works to recruit natural killer cell response is vital for effective vaccination. Table 3 summarizes the
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different antigens being studied for different cancer treatments and their delivery NP conjugate [154].

Table 3. Nanoparticle vaccine delivery for various cancer [154].

Cancer Type Nanoparticles Antigen

Poly(lactic-co-glycolic acid)
Ag, Poly(I:C)
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(PLGA) NPs

Melanoma Liposome TRP2, α GalCer

CNT α CD40, CpG
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Cowpea mosaic virus (CPMV) NPs Empty Cowpea mosaic virus (eCPMV)
Non-small cell lung cancer L-BLP25 liposome MUC1
Ovalbumin (OVA), Monophosphoryl
Breast cancer PLGA-PEG
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lipid A (MPLA), CpG

Prostate cancer Virus-like particle Polyethylenimine-stearic acid (PSA)
Cervical cancer Tumour virus vaccine HPV

An adjuvant is a molecule that increases immunogenicity. They sometimes are lacking in tumour
antigens when presented alone. Commonly used adjuvant in cancer treatment are 3-O-desacyk-40 -
monophosphoryl lipid A (MPLA), CpG oligodeoxynucleotides (ODNs), lipopolysaccharide (LPS),
polyinosinic:polycytidylic acid (poly I:C), and agonists of the stimulator of IFN genes (STING).
Nanomaterials 2020, 10, 1700 21 of 40

When they are internalized in antigen-presenting cells with tumour antigens, they promote anticancer
immune response [155]. Nanoparticles have a multifaceted role in modern immunotherapy. They can
reduce tumour-associated macrophages and act as a tumour suppressor agent, selectively knockdown
Kras oncogene addiction by the nano-Crisper-Cas9 delivery system, and serve as an efficient alternative
to the chimeric antigen receptor [(CAR)-T] [156]. Immunotherapy is one of the effective modalities
for cancer treatment. Targeting the tumour environment along with the immune system is a viable
strategy to use for cancer treatment. Systematic delivery of immunotherapeutic agents to the body

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using NP delivery is of great importance. Liposomes, Au NPs, polylactic-co-glycolic acid (PLGA) NPs,
micelles, iron oxide NPs, and dendrimers are widely used for immunotherapy. Polymeric NPs are the
most commonly used ones in immunotherapy where PLGA is an FDA-approved polymeric carrier.
Table 4 below lists the commonly used NPs used in immunotherapy, their therapeutic agent conjugate,
target, function, and studied tumour model [157].

Table 4. Nanoparticle used in immunotherapy [157].

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NP Materials Therapeutic Agents Target Function Tumour Model
AUNP12 anti-PD-1 Blockage of PD-1/PDL-1 4T1 Subcutaneous
Tumour cells
peptide pathway tumour

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Human epidermal GER2 degradation and
In vitro HER2 Positive
PLGA-based NPs Trastuzumab growth factor 2 antibody-dependent
breast model
(HER2) cell-mediated cytotoxicity
Pam3CSK4 and B16-OVA
CD40 T cell response
pa α-CD40-mAb Subcutaneous tumour
Tumour specific Block TGF-β Signal and
SB505124 TGF-β 1 E.g7-OVA
cytotoxic promote CD8 + T cell
inhibitor Subcutaneous tumour
T-lymphocyte CTLs infiltration
Activation of DCs via Th1
Curdlan and mannan Cytosol of DCs DC2.4 in vitro model
Liposomes cytokine production
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Stimulator of
Tumour Proinflammatory gene
interferon genes B16-F10 Lung
microenvironment induction and production
(STING) agonists and c metastatic tumour
(TME) of immunological memory
GAMP
Antigen-specific cellular C57BL/6 intradermal
Pyranine antigen Cytoplasm of DCs
immunity immunized mice
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Suppression of growth of
4T1 subcutaneous
NLG919/IR780 Lymph node tumour margin in primary
Micelles tumour
tumours
Tumour-associated
ROS inducing ZnPP Activation of NK cells and B16-F10 Subcutaneous
macrophages
PM/PIC T lymphocytes tumour
(TAMs)
Induce systemic
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OVA peptide B-16 OVA

Dendritic cells antigen-specific immune
antigen/CpG adjuvant Subcutaneous tumour
AuNPs response
Imaging and tumour Colon cancer
α-PDL1 Tumour cells
reduction Subcutaneous tumour
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Superparamagnetic DCs and Immune cell activation CT2 Subcutaneous

Fe3 O4 macrophages and cytokine production tumour

Iron Oxide NPs Increased caspase-3

activity and MMTV-PyMT
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Ferumoxytol Macrophages
proinflammatory Th1 Mammary tumour
response
Tumour
Specific binding and OVCAR3
Dendrimers mAbK1/PTX cells—mesothelin
antitumour activity Subcutaneous tumour
receptor
DEC205 monoclonal
Artificial exosomes Dendritic cells Targeting to DCs In vitro studies-DCs
antibody
Nanomaterials 2020, 10, 1700 22 of 40

Cyclic dinucleotides (CDNs) is a potent stimulator of the interferon receptor (STING) agonist.
Its efficacy is limited to micromolar concentration due to the cytosolic residence of STING in the
ER membrane. Biodegradable poly (beta-amino ester) NPs were introduced to deliver CDNs to the
cytosol, which leads to robust immune response > 100-fold lower extracellular CDN concentration
in vitro. This NP-mediated cytosolic delivery for STING agonists synergizes with checkpoint inhibitors
and has the potential for enhanced immunotherapy [158]. A new strategy of cancer immunotherapy
using plant virus-based NPs was proposed. In vaccine development, plant virus has already been

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utilized extensively. Successful employment of plant viruses in cancer treatment has been observed
using hibiscus chlorotic ringspot virus, tomato bushy stunt virus, and red clover necrotic mosaic
virus. Plant viruses offer the advantage of uniformity concerning shape and size and ability to
self assemble into highly repeating nanostructures. They also exhibit structurally defined chemical
attachment sites, cargo capacity, and tolerance against high temperature and pH [159]. Metallic NPs
also have high potential in immunotherapy. Several metallic NPs such as Au NPs have been
studied to be used with several immunotherapeutic agents such as ovalbumin (OVA). Metallic NPs

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have also shown to improve antitumour cytotoxic T cell response. Metallic NPs have advantages
which can be utilized with combination therapy of immunotherapy and PTT [160]. Elimination or
reprogramming of the immune-suppressive tumour microenvironment is a major challenge in

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immunotherapy. Immune checkpoint inhibition targets regulatory pathways in T cells to enhance
tumour response and has been the most successful method in immunotherapy. Some FDA-approved
immune checkpoint agents are ipilimumab against CTLA-4, and pembrolizumab and nivolumab against
PD-1. Lipid-based NPs are generally used to transport these materials to the target site [161]. A study
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showed that R848-loaded β—cyclodextrin NPs can efficiently be delivered to tumour-associated
macrophages in vivo to macrophages to acquire an antitumourigenic M1-like phenotype. The functional
orientation of the tumour immune microenvironment toward an M1 phenotype was achieved through
the administration of CDNP-R848 in multiple mouse models. An improved immune response rate
was observed when combined with immune checkpoint inhibitor anti-PD-1 [162]. Exosomes are
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nanosized particles secreted from most cells. This allows crosstalk between cells and their surrounding
environment through cargo transfer. Tumour cells also secrete exosomes, known as tumour-derived
exosomes. They have tumour modulation activity and can affect the tumour microenvironment and
antitumour response. Their immunological activity influences both innate and adaptive immune
systems, including regulatory T-cell maturation, natural killer cell activity, and anti-inflammatory
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response. Their characteristics allow them to be used for metastasis lung cancer treatment [163].

4. Theranostics
Theranostics involves the administration of a diagnosis agent. They are referred to as a combination
of diagnosis and therapy using the same agent [164].
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4.1. Multimodality Imaging

SPIONs, (Feraheme, FH) and [89 Zr]Zr was used as a nanoplatform for PET and MRI. PET-MRI
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integrates the excellent sensitivity of PET with the spatial resolution and contrast of soft tissue by
MRI. Feraheme can shorten the transverse relaxation time, T2 , and is generally used for dark contrast
enhancement. However, dark contrast is often difficult to implement in clinical settings for applications
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such as detection and diagnosis of metastases in the lymph nodes. FH radiolabelled with OET tracer can
take advantage of highly sensitive bright signals from PET. It can detect the presence of FH in regions,
where the MRI contrast is too low or noisy. Experimental results showed that FH is a very suitable
SPION for chelate-free labelling of PET tracers, and can be used in hybrid PET-MRI [165]. For combined
magnetomotive ultrasound PET/CT and MRI for sentinel lymph nodes, 68 Ga-labelled SPIONs were
proposed. The results showed that the SPIONs provided viable contrast enhancement [166]. TAM is
significantly associated with poor prognosis of tumours. Using super magnetic iron oxide and
perfluorocarbon nanoemulsions, quantitative monitoring of TAM is possible with MRI-based TAM
Nanomaterials 2020, 10, 1700 23 of 40

imaging. A study was conducted using MRI-based measurements of TAMs as a prognostic marker and
PET to observe tumour behaviour with 18 F-2-fluroro-2-deoxy-D-glucose as a radioactive tracer [167].
Ultra-small AGulX NPs are made of polysiloxane and are surrounded by gadolinium chelates. They are
generally obtained via the top-down process. They are the first multifunctional silica-based NPs that
are small enough to escape hepatic clearance. Their hydrodynamic diameter is under 5 nm, and they
have excellent radiosensitizing properties for radiotherapy. They can be used in four different types
of imaging modalities: MRI, SPECT, fluorescence imaging, and CT. A recent study showed that they

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can be used in MRI-guided radiotherapy. The study found that 68 Ga-AGulX@NODAGA has great
potential in PET/MRI-guided radiotherapy. They can be used as a dual modality PET/MRI imaging
agent with passive accumulation in the diseased area [168].
Image-guided radiotherapy can improve cancer outcomes significantly [169–171]. A theranostic
platform and a combination of bismuth and gadolinium were proposed for onsite radiosensitization and
image contrast enhancement. A study showed that NPs provided image enhancement in both CT and
MRI, and tumour suppression with prolonged survival in non-small cell lung carcinoma models with

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minimal off-target toxicity [172]. Mesoporous silica NPs for CT and optical imaging were introduced.
The high density of platinum NPs in the surface of mesoporous silica NPs greatly enhances CT contrast.
NIR fluorescent dye Dy800 was conjugated to the platform to enhance optical imaging contrast. It was

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tested on a breast tumour mouse model. In vivo imaging showed significant enhancement in images
after 24 h injection [173]. A multimodal imaging probe for PET/SPECT and MRI (T2 ) was developed
using SPIONs and deblock copolymer with either methoxy polyethylene glycol or primary amine NH2
end groups. 57 Co2+ ions were used as a radioactive tracer and the study results found the probe to be
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nontoxic [174]. Another biomedical probe with an Au NP platform was introduced that is capable
of coordinating Gd3+ for MRI and 67 Gd3+ for SPECT imaging. The Au NPs had high affinity toward
the gastrin-releasing peptide receptor. These receptors are overexpressed in various human cancer
cells, mainly in PC3 prostate cancer cells [175]. A multifunctional targeting NP probe for pancreatic
cancer was introduced that consists of 1,2 Distearoyl-sn-glycero-3-phosphoethanolamine-N-amino
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(polyethylene glycol)-modified SPIONs, which were conjugated with the plectin-1 antibody. In vivo
optical imaging and MRI show that they highly accumulate in MIAPaCa2 and XPA-1 carcinoma cells.
They can be used as a theranostic tool in fluorescence and MRI to visualize pancreatic cancer [176].
Myocardial infection (MI) is a common disease and has a high mortality rate. MnO-based NPs in
conjunction with MRI and NIR fluorescence imaging can help to combat against MI. MnO possess
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high r1 relaxivity and has none or minimal toxicity. They can be used as an MRI contrast agent and
as a drug carrier due to their preference to accumulate in the infarcted myocardium, as shown in
fluorescence imaging [177]. Dendrimers with size range between 7–12 nm have advantages over other
NPs due to their improved tumour penetration ability and inclusion of a tumour-specific drug release
mechanism. G5 PAMAM dendrimer can be used with a paramagnetic chemical exchange saturation
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transfer (PARACEST) MRI contrast agent in MRI-optical imaging as dual mode MRI-optical glioma
imaging NPs. Experimental results showed they were able to identify glioma tumours at a mm scale
due to the perseverance of the MRI contrast throughout the glioma [178].
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Nanoparticles that have high absorption in the NIR region are valuable in biomedical applications.
Photoacoustic imaging (PAI) is an imaging modality that makes use of optical excitation. The imaging
provides deep tissue penetration and high spatial resolution. In PAI, the photoacoustic signal is
primarily determined by the pulsed laser. Therefore, the contrast agents used in PAI generally can also
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be used in PTT. Mesoporous carbon nanospheres (Meso-CNS), as a stable suspension with broadband
and intense absorption in the UV–vis–NIR region, were studied. The analysis of photothermal
conversion and photoacoustic generation show Meso-CNS possess absorption coefficients that are
1.5–2 times higher than those of CNT and graphene in the broad wavelength region, and comparable
to gold nanorod in both NIR-I and NIR-II region. They can efficiently (35 wt%) load DOX due to
their large surface area, appropriate pore volume, and size. All of these characteristics make them an
excellent theranostic platform [179]. A dual-mode imaging system of photoacoustic microscopy and
Nanomaterials 2020, 10, 1700 24 of 40

fluorescence optical microscopy with Au NPs was also proposed. Gold nanoparticles have a large
absorption coefficient and enough fluoresce emission with a wavelength of 512 nm. They can be used
to label certain drugs in tobacco cells, and also can be used to carry the labelled drug in the target
position [180].

4.2. Image-Guided Therapy

A semiconducting plasmonic nanovesicle was proposed that consisted of semiconducting poly

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(perylene diimide) (PPDI) and poly(ethylene glycol (PEG) tethered to Au NPs (Au@PPDI/PEG).
The complex was highly localized and had a strong electromagnetic field between adjacent Au NPs
in the vesicular shell. The electromagnetic field enhanced the light absorption efficiency of PPDI.
It generates a great photothermal effect. It also provides a strong photoacoustic signal that can be
used in PAI. Overall, the complex has high potential as a theranostic agent [181]. Gold nanorods
in PAI and plasmonic PTT have been studied. The advantageous properties of Au NPs such as

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biocompatibility, tuneable surface plasmonic resonance, and controlled synthesis make them a great
choice for theranostic applications. PAI-guided PTT is possible when the pulse is used to destroy the
cancer cells. This application has great potential to be used for lung cancer [182]. A hybrid reduced
graphene oxide (rGO)-loaded ultra-small plasmonic gold nanorod vesicle (rGO-AuNRVe) had excellent

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photoacoustic signal amplification ability, and the photothermal effect was proposed as a theranostic
tool to be used in PIA, PTT, and chemotherapy. It had high DOX loading capability and efficiency, and it
can unload upon light NIR photothermal heating. This ability makes them ideal for a combination of
photochemotherapy. When rGO-AuNRVe was labelled with 64 Cu, it showed high accumulation in
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U87MG tumours via passive accumulation in PET imaging [183]. Pure bismuth NPs have ultrahigh
x-ray attenuation coefficient and light to heat conversion capabilities. These characteristics make them
suitable to be used in PAI and PTT. In one study, bismuth NPs were able to increase the temperature
by 70 degrees Celsius within 4 min under infrared irradiation in PTT [184]. Carbon nanotubes have
advantageous optical, thermal, mechanical, electrical, and magnetic properties. Some of the applications
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of CNT in biology are as a heating agent, contrast agent, and drug delivery agent. Carbon nanotubes
can increase the temperature in the tissue during laser irradiation in PTT, and at the same time, enhance
photoacoustic signals. The nanotubes can potentially be used as a theranostic agent in PTT and
PAI [185]. A theranostic agent was developed that consists of perfluorohexane liquid and Au NPs
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that make up the core and is stabilized by a polymer shell (poly (lactide-co-glycolic acid)(PLGA)).
When PLGA-Au NPs localize in tumour cells and are exposed to laser pulses, cell viability decreases,
leading to cell death. The study results showed they have viable potential to be used as a PAI and
therapeutic agent for future clinical cancer therapy [186].
Gold nanoparticles have a high atomic number and they strongly absorb low and medium energy
x-rays by the photoelectric effect [187–189]. During the photoelectric effect, characteristic x-rays and
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Auger electrons released in the surroundings are in a short-range. They can cause additional local
damage [190]. Gold nanoparticles can be conjugated to targeting ligands or they can selectively be
accumulated into the tumour via passive permeability and retention effects. Due to these abilities, they
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have high potential to be very effective in tumour radiotherapy augmentation without increasing the
dose to the surrounding normal tissues, and can also be used as a contrast agent in CT, making it an
excellent theranostic tool [191,192]. A hyaluronic acid-functionalized bismuth oxide NP was synthesized
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using a one-pot hydrothermal method used in targeting specific CT imaging and radiosensitizing
of tumour. The integration of hyaluronic acid Bi2 O3 NPs provides solubility in water and excellent
biocompatibility. Targeting mechanism allows them to be taken up specifically by CD44 receptors
overexpressed in cancer cells. HA-Bi2 O3 NPs have high x-ray attenuation efficiency. They also have
ideal radiosensitivity through synergizing x-rays to induce cell apoptosis and arrest cell cycle in a
dose-dependent manner. A study showed that these active targeting NPs provide excellent CT imaging
enhancement and can be used as a theranostic tool [193].
Nanomaterials 2020, 10, 1700 25 of 40

A liposome-coencapsulated DOX, hollow Au NPs, and perfluorocarbon were synthesized into a

theranostic agent. It had an efficient light-to-heat conversion effect under 808 nm NIR laser irradiation
and small size that enabled high accumulation in the tumour sites. It also had an efficient DOX release
and enhanced ultrasound signal. All of these properties make it an excellent theranostic agent in PTT
and ultrasound imaging [194]. Another ultrasonic photothermal agent was introduced that consists of
NBs, graphene oxide, and hairpin sulfate proteoglycan glypican-3 (target molecule). It can work as a
molecularly targeted contrast agent and contrast enhancer for ultrasound imaging. It can also be used

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in combination with ultrasound and PTT [195]. A new NBs–paclitaxel liposome complex for ultrasound
imaging and ultrasound responsive drug delivery was introduced. The complex was 528.7 ± 31.7 nm in
size with paclitaxel entrapment efficiency of 85.4 ± 4.39%, and conjugation efficiency of ~98.7 ± 0.14%
with 200 nm-sized liposomes. When treated with the NBs–paclitaxel liposome, the sonoporation
of MiaPaCa-2 cells had 2.5-fold higher uptake of liposomes compared to the control. It also had
more than 300-fold higher anticancer activity compared to the commercial formulation ABRAZANE.
The conjugate exhibits echogenicity comparable to the commercial ultrasound contrast agent SonoVue,

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where the echogenic stability of NBs–paclitaxel was more than one week. These properties and the
image enhancing properties make it an excellent theranostic agent [196].
Silica NPs have been intensively studied in drug delivery and can be integrated with other

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materials for theranostic capabilities. The MnO/SiO2 core–shell can be used for multimodal imaging.
Its localization can be monitored with MRI and poly (propylene fumarate) scaffolds. The anticancer
drug DOX can be loaded into it. Its porous silica shell enhances the water dispersibility of the core and
minimizes leakage of the core iron [197]. Carbon dots are widely used in optical imaging nanoprobes.
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They are generally used for labelling cells in cancer treatment. A study proposed a gadolinium
complex that consists of carbon nanodots. They have high fluorescent properties, excellent water
solubility, and biocompatibility. They can also be conjugated to apoferritin nanocages for drug loading
capabilities such as DOX. Folic acid can be used as a targeting molecule for MCF-7 cells and the
results showed it is a viable theranostic tool with negligible toxicity [198]. A new iron (III)–tannic
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complex-based NP (Fe–TA NP) was introduced. It had good physicochemical properties with the
capability of inducing autophagy in both hepatocellular carcinoma cells (HePG2.2.15) and normal rat
hepatocytes (AML12). Experimental results showed the Fe–TA NP was capable of inducing HepG2.2.15
cell death via autography and did not affect cell viability in AML12 cells due to much higher uptake
of the Fe-TA NPs by the HepG2.2.15 cells. Enhancement of the T1 MRI contrast was achieved in
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HepG2.2.15 cells due to these circumstances. These results also suggest that the Fe–TA NP can provide
new strategies for combining diagnostic and therapeutic functions for hepatocellular carcinoma [199].
A synergistic platform for synergistic therapy and real-time imaging was studied. It is very
advantageous when treating cancer patients. However, it also faces many challenges for clinical
use. Novel theranostic agent, bismuth sulfide@mesoporous silica (Bi2 S3 @mPs) core–shell NPs were
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introduced to be used in targeted image-guided therapy for EGFR-2 positive breast cancer. The agent
was obtained by decorating polyvinylpyrrolidone with Bi2 S3 NR. It was chemically encapsulated
with a mesoporous silica layer loaded with DOX, an anticancer drug. Trastuzumab was used as a
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targeting molecule that targets EGFR-2. They overexpressed in breast cancer cells. Experimental results
showed the agent has good drug loading capabilities, biocompatibility, strong x-ray attenuation of the
bismuth element, and precise tumour targeting and accumulation. These characteristics allow it to
simultaneously act as a contrast enhancer for CT in deep tissue and as a therapeutic agent in synergistic
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photothermal chemotherapy [200]. Another synergistic treatment platform was developed for PAI,
targeted PTT, and chemotherapy. Its use was studied in triple-negative breast cancer. The nanoplatform
was composed of magnetic hybrid NP (lipid, doxorubicin), gold nanorods, and an iron oxide nanocluster
(LDGI) loaded with mesenchymal stem cells. LDGIs have efficient cellular uptake by stem cells and
are still be able to maintain their cellular function. LDGI can simultaneously release drugs and achieve
photothermal properties upon light irradiation. The drug can then enter the cell and activate cell
apoptosis. Mesenchymal stem cells have the highest enhanced migration and penetration abilities in
Nanomaterials 2020, 10, 1700 26 of 40

tumours. It also showed the best antitumour efficacy in chemophotothermal therapy compared to
other treatment groups in triple-negative breast cancer [201]. Another study showed a new strategy to
use gold nanorod conjugated with polyacrylic acid/calcium phosphate (AuNR@PAA/CaP) yolk-shell
NPs for dual-mode x-ray CT/PAI and PTT. It possesses extremely high DOX loading capabilities,
pH and NIR dual responsive drug delivery ability, and high photothermal conversion properties.
At low pH, the CaP shell takes damage and releases DOX. When the conjugate is exposed to NIR
irradiation, burst-like drug release occurs [202]. A human cytokine-induced killer cell (CIK) was

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loaded with gold nanorods that were used for targeted PAI, enhanced immunotherapy, and PTT
for gastric cancer. The study results showed that CIK-labelled gold nanorods actively target gastric
cancer MGC803 cells and activate cell apoptosis under NIR laser irradiation. The results also showed
CIKAuNR can actively target and image subcutaneous gastric cancer vessels via PIA after 4 h of
injection. It can also enhance immunotherapy by regulating cytokines and kill gastric cancer cells by
PTT [203]. SPIONs have high r1 and r2 relativities and they can be completely eliminated from the body.
They can accumulate in cancer through passive targeting permeability, and retention effects or active

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targeting. The magnetite and maghemite cores of SPIONs can easily be detected with MRI. Polymer
coating SPIONs can be loaded with therapeutic agents to facilitate MRI-guided drug delivery, PTT, PDT,
gene therapy, or magnetic hyperthermia. SPIONs-delivered chemotherapy has high potential, and a

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variety of small chemotherapeutic agents have been incorporated into SPIONs-based nanocarriers
through a cleavable linker or π–π stacking. They can increase blood circulation half-life, promote
tumour retention, and enable real-time drug tracking. Accumulation of SPIONs in the spleen or
other reticuloendothelial systems can exert toxic effects after multiple-dose administration. Smart or
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responsive SPIONs have been developed to mediate that problem. SPIONs can also be used as a carrier
for small interfering RNA (siRNA) or microRNA (miRNA), which can protect the ribonucleic acid and
prevent enzyme degradation [204].

4.3. Combination Therapy

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Combination therapy provides treatment of several malignancies to improve clinical outcomes.

They generally induce synergistic drug action and try to work around drug resistance. There are
several NPs used in combination therapy such as liposomes. Various liposomal formulation of DOX
include DaunoXome, Doxil, DepoCyt, and ONCO-TCS. Liposomes are one of the most established drug
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delivery vehicles, with many clinical products. Some other NPs that are used in combination therapy
are polymeric NPs. They have high thermodynamic and kinetic properties used in site-specific delivery
of the anticancer drug to tumours. Metallic NPs, dendrimers, nanodiamonds, carbon NPs, and CNT are
some other ones used in combination therapy [205]. A mesoporous NP-based drug delivery system was
introduced to be used for real-time imaging in photothermal/photodynamic therapy and nanozyme
oxidative therapy. In one study on synthesized mesoporous carbon–gold hybrid nanozyme nanoprobes,
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carbon nanospheres were doped with small Au NPs, and stabilized with a complex of reduced serum
albumin and folic acid. They were then loaded with IR780 iodide. Their large surface area and
numerous -COOH groups allowed for chemical modification for numerous targeting molecules, load
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abundant NIR dye, and photothermal agents. Small Au NPs were utilized as nanozymes to catalyze
H2 O2 located in the tumour cells to generate OH for intracellular oxidative damage to the tumour.
In vivo and vitro results showed the nanoprobe had excellent tumour targeting efficacy, long tumour
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retention, and favorable therapeutic effect [206]. For combined PDT/PTT with photodecomposable,
photothermal, and photodynamic properties, SP3 NPs were prepared from self-assembled PEGylated
cypate that consists of PEG and ICG derivate. It can generate singlet oxygen for PDT and photothermal
effect for PTT. It has high accumulation in tumour due to PEGylated surface and small size (~60 nm).
All of these properties make it a potential candidate to be used in image-guided PDT/PTT [207].
Chemotherapy is one of the most common cancer treatment options, but it has showed off-target
toxicity issues. Theranostic NPs integrates diagnostic and therapeutic functions within one platform,
increases tumour selectivity for more effective therapy, and assists in diagnosis and monitoring
Nanomaterials 2020, 10, 1700 27 of 40

of therapeutic response. Core–shell NPs were synthesized by nanoprecipitation of blends of the

biodegradable and biocompatible amphiphilic copolymers poly (lactic-co-glycolic acid)-b-ply-L-lysine
and poly (lactic acid)-b-ply (ethylene glycol). The NPs were spherical and had an average size of
60–90 nm. DOX was encapsulated in the core of the NPs. The results showed a 33-fold increase
in NIR fluorescence in the mouse model and found it to be suitable for a controlled drug delivery
system and a contrast agent for imaging cancer cells [208]. PTT in combination with chemotherapy
can trigger powerful antitumour immunity against tumours. Polydopamine-coated spiky Au NPs

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with high photothermal stability were introduced for PTT and chemotherapy. A single round of
PTT combined with a subtherapeutic dose of DOX can yield good antitumour immune response and
eliminate primary and untreated distant metastasis in 85% of animals bearing CT26 colon carcinoma.
Their efficacy was studied against TC-1 submucosa-lung metastasis, a highly aggressive model for
advanced head-and-neck squamous cell carcinoma [209]. Monotherapy of cancer is usually subjected
to some sacrifice and as such, limits therapeutic benefits. Generally, in the form of systemic toxicity,
a combination of chemo and PTT elevates the therapeutic benefits and is generally considered a

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maximal cooperation effect achieved in combination therapy. Silica NPs with Cetuximab to target the
epidermal growth factor receptor were developed. They had a high drug loading capacity of Cet-SLN
that can be used to encapsulate photothermal agent ICG. It can simultaneously codeliver ICG and Cet

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for combinational chemophotothermal therapy of breast cancer [210]. Approximately 90% of the cancer
therapeutic failure in patients is due to chemoresistance. Some cancer cells such as progenitor cells
or cancer stem cells develop radioresistance from a variety of chemotherapy agents. Chemo agents
generally aim to destroy rapidly dividing cells and do not have much effect on undifferentiated
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cancer stem cells. Hepatocellular carcinoma is responsible for the third leading cause of cancer-related
death and the fifth most common type of cancer. Gold nanorods have been studied to provide a
solution. Gold nanoparticles in conjunction with PTT can destroy these cells and gold nanorods can
provide suitable contrast agents for PAI. Gold nanoparticles can also act as a carrier. They can carry
therapeutic agents such as Adr when in conjunction with EpCAM antibody on the surface of the
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nanosystem. Adr/AuNPs@Pms-antiEpCAM can specifically target cancer stem cells and enhance the
concentration of drugs in the tumour. This complex can be useful as a future theranostic tool [211].
Modification of NPs allows administration of the drug across the brain and provide a theranostic
platform for Alzheimer’s, Parkinson’s, Huntington’s, and epilepsy disease. NPs can be used as a
carrier to get past the blood–brain barrier and deliver the drug to the brain [212].
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Photoacoustic and fluorescence imaging in NIR-II hold great potential due to their noninvasive
nature and excellent spatial resolution properties. NIR-II is superior in biological imaging due to its
higher signal-to-noise ratio and deeper tissue penetration. Photoacoustic imaging in NIR-II allows
direct and wide visualization of dynamic biological tissues with high spatiotemporal resolution and
sensitivity. It cannot provide comprehensive and accurate diagnosis information, so fluoroscopic
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imaging in NIR-II can make up the missing information in this dual imaging system. It can be used to
facilitate image-guided synergistic chemophotodynamic therapy using gold nanorods. It can also be
used as a carrier and allow precise controlled 1 O2 drug release [213]. Nanoscale coordination polymer
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core–shell NPs carry oxaliplatin in the core and photosensitize the pyropheophorbide–lipid conjugate in
the shell for effective chemotherapy and PDT. The synergy between oxaliplatin and pyrolipid-induced
PDT kills tumour cells and provokes an immune response. This results in calreticulin exposure on the
cell surface, antitumour vaccination, and an abscopal effect [214].
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Photothermal therapy can be an effective antitumour therapy but it may not eliminate tumour
cells. This can lead to the risk of recurrence or metastasis. Photothermal therapy in combination with
immunotherapy can minimize that risk. Polydopamine-coated AI2 O3 NPs were introduced for this
type of combination therapy. NIR laser irradiation can kill the majority of the tumour tissue via PTT.
It also releases tumour-associated antigens. The AI2 O3 within the NPs, together with CpG that acts as
an adjuvant to trigger robust cell-mediated immune responses, can help eliminate the residual tumour
cells. Fifty percent of mice, after going through combined therapy, achieved goal tumour eradication
Nanomaterials 2020, 10, 1700 28 of 40

and survived for 120 days, which was the end goal of the experiment [215]. Photothermal therapy can
be combined with blockage checkpoints to achieve an even more enhanced antitumour effect. Table 5
below summarizes different NPs that can be used in photothermal immunotherapy [216].

Table 5. Nanoparticles used in photothermal therapy (PTT) immunotherapy [216].

Checkpoint
Photothermal NPs Effector Cells Tumours
Blockade

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Prussian blue NPs Anti-CTLA-4 CD4+ /CD8+ T cells Neuroblastoma
4T1 murine breast tumour,
PEGylated single-walled DCs, CD4+ /
Anti-CTLA-4 murine B16 musculus skin
nanotubes CD8+ T cells, CD20+ TILs
melanoma
DCs, CD4+ /CD8+ , memory 4T1 murine breast tumour,
PLGA-ICG-R837 NPs Anti-CTLA-4
T cells CT26 colorectal cancer

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CD4+ /CD8+ T cells, CD19+
Gold nanostars Anti-PD-L1 MB49 bladder tumour
B cells

ICG is a photothermal agent and imiquimod (R837) is a toll-like receptor-7 agonist. In one study,

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they were coencapsulated by poly (lactic-co-glycolic) acid (PLGA). The formed NPs were composed
purely by three clinically approved components that can be used for NIR laser-triggered photothermal
elimination of primary tumours. This generates tumour-associated antigens, which in the presence
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of adjuvant R837-containing NPs, show vaccine-like functions. In combination with the checkpoint
blockade using anticytotoxic T-lymphocyte antigen-4 (CTTLA4), the generated immunological
responses will be able to eliminate remaining tumour cells and will be very useful in metastasis
inhibition [217]. Metastatic breast cancer is one of the most devastating cancers and has very limited
therapeutic options. Nanoparticle-based platforms can offer some therapeutic options for it with
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different combinations of therapy. The chemotherapeutic drug DOX can be delivered using NPs.
PTX formulated with albumin to form NPs is currently used in the clinic for breast cancer therapy.
siRNA can also be delivered using NPs for gene therapy. Nanoparticles offer an option for photothermal
therapy and magnetothermal therapy. They can also be used as a contrast enhancement agent for
image-guided radiotherapy [218]. Gastric cancer is the second most malignant tumour in the world.
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HER-2 is one of the key targets for gastric cancer therapy. A gold nanoshell drug carrier was developed
for delivery of immunotherapeutic agent and selective photothermal release of genes that targets HER-2
and the immunologic adjuvant CPG sequence in gastric tumour cells. This allows multidimensional
treatment strategies such as gene, immune, and PTT. The study results showed good gene transduction
ability and combined treatment effect [219]. A nanosystem consisting of ER targeting pardaxin peptides
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modified ICG conjugated to hollow gold nanospheres, together with oxygen delivering hemoglobin
liposome was studied in PDT, PTT, and immunotherapy. It induces robust ER stress and calreticulin
exposure on the cell surface under NIR light irradiation. CRT, a marker for ICD, acts as an eat-me signal
to stimulate the antigen-presenting function of dendritic cells. It triggers a series of immunological
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responses including cytotoxic cytokine secretion and CD8+ T cell proliferation [220]. A theranostic
nanoplatform that was capable of PAI, as well as a combination of gene and photothermal therapy,
were studied. A gold nanorod was coated with dipicolyl amine, which forms stable complexes with
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Zn2+ cations and yields a Zn (II) dipicolyl amine gold nanorod. It has a strong complexation with
anti-polo like kinase 1 siRNA used for gene silencing. The Au NPs can act as a photothermal agent as
well as an enhancer for photoacoustic imaging upon laser irradiation. Experimental results showed
that they yield significant antitumour activity in the PC-3 tumour mouse model [221].

5. Conclusions
Recent advances in nanotechnology have resulted in great progress of synthetic techniques,
which benefit from the design of many nanomaterials, such as nanoparticles, nanocages, nanodiamonds,
Nanomaterials 2020, 10, 1700 29 of 40

nanoshells, and nanotubes. These nanomaterials can act as very effective contrast agents in various
medical imaging modalities and provide a large number of options in modern cancer therapy.
The nanomaterials allow delivery of many drugs to target sites that otherwise would not be possible
and provide a fundamental basis for some cancer therapy that is showing promising clinical outcomes.
It is expected that continuous discovery in nanotechnology will significantly influence future cancer
therapy and medical imaging. However, some of the limitations of nanomaterials as drug carriers,
contrast agents, and sensitizers, such as cytotoxicity and nonbiodegradability, should be studied further

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in order to minimize the side effects on humans.
For the transition of nanomaterial applications in biomedical imaging and cancer therapy into
commercial clinical practice, it can be seen that many in vitro and in vivo studies have shown promising
results. However, numerous challenges, such as physicochemical properties, drug metabolism,
cytotoxicity and biocompatibility, pharmacokinetic screening, surface engineering, in vivo efficacy,
nanomaterial uptake, immunogenic issues, and preparation costs, still remain. The mechanisms of
action such as the potential impact on the cellular communication, which would limit its clinical

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transformation, are still unclear. Based on the above challenges, possible future directions include
further optimizing various nanomaterials and elucidating the precise mechanisms between the cell
and nanomaterials, to achieve better imaging and therapeutic effects, and accelerate the translation of

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nanomaterials into clinical practice.

Author Contributions: Methodology, J.C.L.C. and S.S.; writing-original draft preparation, S.S.; writing—review
and editing, J.C.L.C.; supervision, J.C.L.C. All authors have read and agreed to the published version of
the manuscript.
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Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.

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