An Overview on Nano Materials for Bio Medical Application

8/6/2019 An Overview on Nano Materials for Bio Medical Application

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An overview on

Nanomaterials for Biomedical Application

By

Jagannath Sardar

(Roll No.: 09610309)

PhD Scholar

Department of Mechanical Engineering

Indian Institute of Technology Guwahati

October, 2009


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Contents Page

1. Introduction 1

2. Classification of Nanomaterials 3

2.1 Carbon Based Materials 3

2.2 Metal Based Materials 4

2.3. Dendrimers 4

2.4. Quantum dots 6

3. Structures of Nanomaterials 6

3.1 Some general structures of well known nanomaterials 7

4. Important nanomaterials for biomedical application 8

5. Synthesis of Nanomaterials 10

5.1 Gold nanomaterials synthesis 10

5.2 Carbon nanomaterials synthesis 12

5.3 Synthesis of Quantum Dots 15

6. Nanomaterials in Biomedical Applications 17

6.1 Drug Delivery 17

6.2 Disease detection 25

6.3 Tissue Engineering 26

6.4 Diagnosis and treatment 28

7. Conclusion 32

8. References 33


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1. Introduction:

The National Nanotechnology Initiative (NNI) subcommittee has given a definition of

Nanotechnology as: nanotechnology is the understanding and control of matter at dimensions of

roughly 1 to 100 nanometers, where unique phenomena enable novel applications. A nanometer

is one billionth of a mater; a sheet of paper is about 100000 nanometers thick. Encompassing

nanoscale science, engineering and technology, nanotechnology involves imaging, measuring,

modeling and manipulating matter at this length scale [1, 2].

Figure 1.1. Nanoparticles in comparison with other biological entities

Nanotechnology has been developed in many areas over the decades, one of the most important

areas of this technology is nanomaterials level, which plays an important role in biomedical

applications.

Biomedical Nanotechnology is the unification of biotechnology and nanotechnology, including

biomedical nanometrics and nano-materials. Diagnostics, drugs delivery, and prostheses &

implants are three major areas where nanotechnology is entering biomedical areas. Biomedical

Nanotechnology is attracting increasing interest as an emerging interdisciplinary research field

straddling nanotechnology and biotechnology. As tools for combining nanotechnology with

biomedical science, information techniques and algorithms appear to be gaining importance in

biomedical nanometrics and nano-materials, with applications from the storage and reproduction


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of genetic information to the control of developmental processes to sophisticated DNA-based

computation and engineering [3].

Venkat S. Kalambur and John C. Bischof had explain in their presentation as a Magnetic

nanoparticles can be potentially used in the targeted delivery of therapeutic agents in vivo, in the

hyperthermic treatment of tumors, in magnetic resonance imaging (MRI) as contrast agents andin the biomagnetic separations of biomolecules. An understanding of the movement, heating and

visualization of these nanoparticles in physiological systems in vitro and in vivo is required to

tailor these nanoparticles for a few of these applications. Secondly, a characterization of the

biodistribution and injury in vitro and in vivo are required when these nanoparticles are used as

therapeutic agents in hyperthermia and drug delivery [4].

Many researchers have discussed about the affection of nano biomaterials in pharmaceutical and

biological applications. For instance some of the recent developments for medicine applications

are; tissue engineering, detection of protein and cancer therapy, drug delivery systems and

medical imaging for cancer diagnosis. One of growing area is drug delivery system with benefit

of targeting a specific cell for delivery with more therapy efficacy.

For biomedical point of view, the cell parts of the organism are the small entity, about10um or

sometimes even smaller which requires small dimensions of nano size application of materials

which is enormous characteristics. Some important applications of the nano size materials are as

- Fluorescent biological labels

- Drug and gene delivery

- Bio detection of pathogens

- Detection of proteins

- Probing of DNA structure

- Tissue engineering

- Tumour destruction via heating (hyperthermia)

- Separation and purification of biological molecules and cells

- MRI contrast enhancement

- Phagokinetic studies etc. [5].

In this scope, we will discuss about nanomaterial for medical and biological applications along

with salient overview with recent developments of the nanomaterials.


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2. Classification of Nanomaterials:

Nanoparticles are constituted of several tens or hundreds of atoms or molecules and can have a

variety of sizes and morphologies (amorphous, crystalline, spherical, needles, etc.). Some kinds

of nanoparticles are already available commercially in the form of dry powders or liquid

dispersions. The latter is obtained by combining nanoparticles with an aqueous or organic liquid

to form a suspension or paste. It may be necessary to use chemical additives (surfactants,

dispersants) to obtain a uniform and stable dispersion of particles. With further processing steps,

nanostructured powders and dispersions can be used to fabricate coatings, components or devices

that may or may not retain the nanostructure of the particulate raw materials. Industrial scale

production of some types of nanoparticulate materials like carbon black, polymer dispersions or

micronised drugs have been established for a long time [6].

Nanomaterials can be classified in different ways. Here we can classify as nanomaterials are four

main types:

1. Carbon Based Materials

2. Metal Based Materials

3. Dendrimers

4. Quantum Dots

2.1 Carbon Based Materials:

These nanomaterials are composed mostly of carbon, most commonly taking the form of a

hollow spheres, ellipsoids, or tubes. Spherical and ellipsoidal carbon nanomaterials are referred

to as fullerenes, while cylindrical ones are called nanotubes. These particles have many potential

applications, including improved films and coatings, stronger and lighter materials, and

applications in electronics.

Apart from that carbon nanofibres are also in this category.

Linear nanostructures such as nanowires, nanotubes or nanorods can be generated from different

material classes e.g. metals, semiconductors or carbon by means of several productiontechniques. As one of the most promising linear nanostructures, carbon nanotubes can be

mentioned, which can occur in a variety of modifications (e.g. single- or multi-walled, filled or

surface modified). Carbon nanotubes are expected to find a broad field of application in

nanoelectronics (logics, data storage or wiring, as well as cold electron sources for flat panel

displays and microwave amplifiers), and also as fillers for nanocomposites for materials with


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special properties. At present, carbon nanotubes can be produced by Chemical vapor deposition

(CVD) methods on a several tons per year scale and the gram quantities are already available

commercially [7].

2.2 Metal Based Materials:These nanomaterials include quantum dots, nanogold, nanosilver and metal oxides, such as

titanium dioxide. A quantum dot is a closely packed semiconductor crystal comprised of

hundreds or thousands of atoms, and whose size is on the order of a few nanometers to a few

hundred nanometers. Changing the size of quantum dots changes their optical properties [6].

In this category, another commercially important class of nanoparticulate materials are metal

oxide nanopowders, such as silica (SiO2), titania (TiO2), alumina (Al2O3) or iron oxide (Fe3O4,

Fe3O3). But also other nanoparticulate substances like compound semiconductors (e.g. cadmium

telluride, CdTe, or gallium arsenide, GaAs) metals (especially precious metals such as Ag, Au)

and alloys are finding increasing product application.

2.3. Dendrimers:

These nanomaterials are nanosized polymers built from branched units. The surface of a

dendrimer has numerous chain ends, which can be tailored to perform specific chemical

functions. This property could also be useful for catalysis. Also, because three-dimensional

dendrimers contain interior cavities into which other molecules could be placed, they may be

useful for drug delivery.


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Figure 2.1. Dendrimers Structures

Dendrimers have unique characteristics including monodispersity and modifiable surface

functionality, along with highly defined size and structure. This makes these polymers attractive

candidates as carriers in drug delivery applications. Drug delivery can be achieved by coupling a

drug to polymer through one of two approaches. Hydrophobic drugs can be complexed within

the hydrophobic dendrimer interior to make them water-soluble or drugs can be covalently

coupled onto the surface of the dendrimer. Using both methods we compared the efficacy of

generation 5PAMAM (Poly amidoamine) dendrimers in the targeted drug delivery of

methotrexate coupled to the polymer. The amine-terminated dendrimers bind to negatively

charged membranes of cells in a non-specific manner and can cause toxicity in vitro and in vivo

[8].

We will discuss in details later on the Dendrimers in drug delivery.


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2.4. Quantum dots:

Quantum dots are spherical nano-sized crystals. They can be made of nearly every

semiconductor metal (e.g., CdS, CdSe, CdTe, ZnS, PbS), but alloys and other metals (e.g. Au)

can also be used. The prototypical quantum dot is cadmium selenide (CdSe). Quantum dots

range between 2 and 10 nm in diameter (10 to 50 atoms). Generally, quantum dots consist of asemiconductor core, over coated by a shell (e.g., ZnS) to improve optical properties, and a cap

enabling improved solubility in aqueous buffers (figure 2.1).

Figure 2.1. Schematic representation of a quantum dot. The cadmium selenide core is surroundedby a shell of zinc sulphide. Finally, a cap can be encapsulate the binary quantum dot by different

material such as silica. The diameter of quantum dots ranges between 2-10 nm

Apart from those major classifications there are several categories of nanomaterials are available,

such as: Nanopowders, Nanocapsules, Nanoporous materials, Nanocomposites, Thin Films etc.

3. Structures of Nanomaterials:

Nanoparticles are designed and prepared with molecule and particle structures that can exibit

functions desired for applications. The size and shape of the prepared particles are primarily

important in the function adaptation [9]. The formation of condensed particles, the volume

universally shows quite a pronounced tendency to approach a minimum, which is best achieved

through the formation of one crystal lattice or another. Various pseudoclose packings can also be

formed, especially when crystalline or quasicrystalline nanoparticles have sufficiently small sizes

[10]. Knowledge on the structural features of nanoparticles is important for any technical and

sophisticated application. These structural features may be determined by the analysing the


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Fourier transformation of the diffraction pattern, which yields the radial distribution function,

also called the pair distribution function [11].

3.1 Some general structures of well known nanomaterials:

Figure 3.1. Different Nanostructures [1, 12]

Gold NanoparticlesSilver Nanoparticles

NanosilicaSilver Nanoparticles

Dendrimer

Quantum DotB-Cd, Y-Se, R-ElectronsDNA strandSilicon-carbide nanowires


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4. Important nanomaterials for biomedical applications:

For biomedical application there are a number of nanomaterials are being used. Some of the

important nanomaterials are listed below and has reviewed on their characteristics and surface

fictionalization in brief.

One of the most important materials is metal nanoparticles, such as Gold (Au) and Silver (Ag)

nonparticles are excellent nanomaterials providing a powerful platform in biomedical

applications of biomolecular recognition and sensing, drug delivery, and imaging.

Metal nanoparticles conjugates with activated enzyme through functionalized Thiol Ligands

(figure 4.1). Similarly Partha Ghosh et al has shown an image on an enzymatic activity of gold

nanoparticles in figure 6.

Figure 4.1 Metal NPs are used as a chemical scaffold to regulate the enzymatic activity

Numerous examples can be found in the literature where bioconjugated Au nanoparticles are

used as colorimetric biosensors detecting proteins, viruses, and bacteria at an extremely sensitive

level. An additional advantage of nanoparticles is that the multiple ligands presented on the

nanoparticle surface could drastically enhance affinities of specific monovalent interactions via

the multivalent binding between NPs and the biological target [13].

Partha Ghosh et.al [14]. has reviewed Gold nanoparticles provide non-toxic carriers for drug and

gene delivery applications.


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Figure 4.2. Various applications of gold nanoparticles in therapy

With these systems, the gold core imparts stability to the assembly, while the monolayer allows

tuning of surface properties such as charge and hydrophobicity [14].

Another important material is Quantum dots (QDs). It has zero-dimension materials exhibiting

quantum confinement in all three spatial dimensions. They are semiconductor nanocrystals

whose bandgap depends on the size of the QDs. The energy gap increases with decreasingparticle size, and therefore smaller QDs emit light at higher energy, ie, lower wavelength and

blue-shift, whereas larger QDs absorb and fluoresce at longer wavelengths and red shift. QDs

have broad excitation spectra yet narrow and tunable emissions, and have thus been widely used

as optical labels in a wide range of biomedical applications including immunoassays for proteins,

nucleic acids, bacteria and toxin analysis [15]

Magnetic nanoparticles of iron oxides have a long history of investigation and have shown

remarkable potentials in biomedical research. A unique characteristics of magnetic particles is

their ability to move simply by the influence of an external magnetic field. Magnetic

nanoparticles with the appropriate surface chemistry have thus attracted increasingly interests

and have been widely used in the life sciences [16] including magnetic resonance imaging (MRI)

contrast enhancement [17], drug delivery, hyperthermia, cell separation [18], and tissue repair.

Both inherent properties of magnetic nanoparticles (magnetic, non-porous, controllable size and

high stability) and modification of their surfaces play crucial roles in such applications.


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Superparamagnetic iron oxide nanoparticles can furthermore improve the diagnostic value by

enhancing the MRI contrast on surrounding healthy and pathological tissues, increasing the MRI

resolution at the microscopic-level [19].

One of the most important materials is Carbon nanotubes (CNTs) which are well-ordered,

hexagonal lattice networks of carbon atoms, which can be viewed as one or more layers ofgraphene sheets rolled up into a cylinder. The diameter of CNTs varies depending on the number

of layers, and CNTs of high aspect ratios can be fabricated [1]. CNTs have been the subject of

intense interest due to their superb electrical and thermal conductivities, exceptional mechanical

strength, and excellent chemical and thermal stability [20]. Biomedical applications of CNTs

require the functionalization of the materials with appropriate ligands rendering them bioactive

and at the same time compatible with the biological environment (58-60). A number of methods

have been developed to conjugate carbohydrates, peptides, and proteins on CNTs [21].

Apart from those materials there are many important materials are also used in biomedical

sectors such as nanosilica, dendrimers, nanogel, nanoclay and so on so forth.

5. Synthesis of Nanomaterials:

In this occasion we will discus the synthesis process of some important nanomaterials.

5.1 Synthesis of Gold nanomaterials:

Several research groups have fabricated delivery systems based on GNPs bearing functional

moieties, which are anchored with thiol-linkers, in their monolayers. A wide variety of

monolayer protected clusters (MPCs) can be formed rapidly and in scalable fashion using the

one-pot protocol developed by Schiffrin et al. in 1994 [22]. In this preparation, AuCl4-

salts are

reduced with NaBH4 in the presence of the desired thiol capping ligand or ligands (figure 5.1).

The core size of the particles can be varied from 1.5 nm to ~6 nm by varying the thiolgold

stoichiometry [14].


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Figure 5.1. Formation of MPCs using the Schiffrin reaction and MMPCs using the

Murray's place-exchange reaction.

Ashkan Tavakoli Naeini et al. [23] said that one of the most widely used methods is the

reduction of tetrachloroaurate ions (AuCl4-) in aqueous medium using sodium citrate to generate

particles with diameters typically ranging from 10 to 100 nm. Although this method has good

control over producing a particular particle size, it is limited to the synthesis of larger particles.

The Brust method and various modifications are useful for the generation of Au NPs having core

sizes ranging from 1 to 4 nm. In the Brust method, the transfer of AuCl4 into toluene or

chloroform is performed using tetraalkylammonium bromide followed by reduction with sodium

borohydride in the presence of alkylthiols. On the other hand Linear-dendritic copolymers

containing hyperbranched poly (citric acid) and linear poly(ethyleneglycol) blocks (PCA-PEG-

PCA) are used as reducing and capping agents to synthesize and support gold nanoparticles (Au

NPs).Another method of synthesis of ultra fine gold nanoparticles created by the Liverpool

University team. They created a gold nanoparticle one thousand times smaller in diameter than a

human red blood cell, and attached it to a gold substrate by means of a 'molecular wire'. The wire

was synthesised by Professor Don Bethell [24], who explains: "Its role was to act as a 'spacer'

between the nanoparticle and the conducting substrate, and also as a chemical glue, since both

ends were composed of sulphur-containing thiols which adhere readily to gold." They have given

a schematic to synthesis gold nanoparticles in the figure 5.2.


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Figure 5.2. Nanoscale redox gate constructed with a single gold nanoparticle

5.2 Synthesis of Carbon nanomaterials:

Synthesis of carbon nanotubes can be done by different methods. The three most commonly used

methods are the arc discharge, laser ablation, and chemical vapor deposition (CVD) techniques.

While the arc and laser methods can produce large quantities of carbon nanotubes they lead to

resilient contaminants, including pyrolytic and amorphous carbon [25], which are difficult to

remove from the sample. Such impurities result in low recovery yield for the carbon nanotube

product [26]. However, recent advances in scaling up these methods, as well as development

new fabrication methods such as high pressure carbon monoxide (HiPCO), have created

commercial supplies of carbon nanotubes with more than 90% purity with competitive prices. In

contrast, the less scalable CVD process offers the best chance of obtaining controllable routes for

the selective production of carbon nanotubes with defined properties [27]. CVD is catalytically

driven, wherein a metal catalyst is used in conjunction with the thermal decomposition of

hydrocarbon feedstock gases to produce carbon nanotubes. In most cases, the resultant growth of

nanotubes occurs on a fixed substrate within the process. Figure 5.3 illustrates a typical CVD

process for the generation of SWNTs. SWNTs are synthesized by the reaction of a hydrocarbon

(e.g., CH4) vapor over a dispersed Fe catalyst. The synthesis apparatus consists of a quartz tube

reactor inside a combined preheater and furnace set-up. The preheat section is operated


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at~2000C. The catalysts are deposited and then hydrocarbon vapors are carried into the reaction

zone of the furnace.

Figure 5.3. Schematic of a chemical vapor deposition (CVD) reactor that uses a two-zonefurnace. Carbon nanotubes grow on the substrate placed inside the quartz tube [25].

Carbon nanofibres are a form of vapor-grown carbon fibre which is a discontinuous graphite

filament produced in the gas phase from the pyrolysis of hydrocarbons [1]. Carbon nanofibres

have transport and mechanical properties that approach the theoretical values of single crystal

graphite, similar to the fullerness, but they can be made in high volumes at low cost ultimately

lower than that of conventional carbon fibres.

Yan Yan et al [28], explained that the carbon nanoparticles are prepared in solution by twomethods: solvothermal synthesis and hot injection.

In solvothermal synthesis amphiphilic triblock copolymer P123 (0.54.5 g) was dissolved in 40

mL of toluene with stirring until a homogeneous solution was formed. Mesophase pitches (MPs)

(0.15 g) were added to the solution, followed by sonicate for the dispersion and stirring for 1 h.

The mixture was centrifuged to separate the insoluble species and a dark brown homogenous

solution was obtained for the reaction. Twenty-five milliliters of the above homogenous solution

was added into a teflon-lined stainless steel autoclave with capacity of 30 mL. The autoclave was

kept at 2000 C for 40 min and then cooled to room temperature naturally. The resultants were

collected and centrifuged to get black powders. The products were rinsed several times with

acetone and dried in ambient temperature.

In Hot injection synthesis, MPs (0.25 g) were triturated and dissolved in 5 mL of oleic acid. The

indiscerptible solid was then removed by centrifugation (ca. 50% of the MPs could be dissolved

in oleic acid). This cold MP stock solution was quickly injected into 50 ml of oleic acid solvent


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containing 0.763.04 mmol of H2SO4 at 1800C with N2 flowing. The reaction mixture was stirred

vigorously at 1800C for 530 min. The products were then collected by centrifugation and

washing as described above.

Carbon nanofibres are manufactured by pyrolysis method which is illustrated in the figure 5.4.

Figure 5.4. Pyrolysis for carbon nanofibres [1]

At the same time Ben Wong et al. [29] has given a synthesis procedure to produce gold

nanoparticle composite. They have shown One gram of substrate, either silica or polymer was

placed into a sintered container and loaded within a 10 cm3 autoclave. Approximately 100 mg of

gold complex was added into the autoclave outside of the sintered container. There was no direct

contact between the substrate and the gold precursor. The autoclave was filled with CO2 and the

pressure was increased to 27.58MPa (4000 psi) at 313 K. CO2 was supplied to the autoclave by

means of a refrigerator/compressor pump (NWA PM-101) connected to a chromatography grade

CO2 cylinder. The temperature was controlled by means of an externally situated thermocouple

connected via a feedback loop to a set of heating cartridges. The heating cartridges were located

within an aluminium heating block surrounding the autoclave. After 24 h of processing, the CO2was released from the autoclave over a period of approximately 20 s.


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5.3 Synthesis of Quantum Dots:

Quantum dots are specially engineered nanoscale crystals of semiconductor compounds. The

name comes from the fact that their infinitesimal size enables a quantum electronics effect that

causes the crystals to fluoresce brilliantly at specific, sharply defined colors. Bright, stable, tiny,

and tunable across a broad spectrum of colors, quantum dots that are engineered to attach

themselves to particular proteins have become a popular research tool in areas such as cancer

research for detecting, labeling, and tracking specific biomarkers and cells.

Making good quantum dots for biological research is complex. First a semiconductor

compoundtypically a mixture of cadmium and seleniummust be induced to crystallize into

discrete nanocrystals of just the right size. Cadmium is toxic, and the compound also can oxidize

easily (ruining the effect), so the nanocrystals must be encapsulated in a protective shell such as

zinc sulfide. To make them water soluble for biological applications, a short organic molecule

called a ligand is attached to the zinc atoms. The organic ligand also serves as a tether to attach

additional functional molecules that cause the dot to bind to specific proteins.

The accepted commercial method uses a high-temperature reaction (about 300 degrees Celsius)

that must be carefully controlled under an inert gas atmosphere for the crystallization and

encapsulation stages. An intermediate ligand material that can tolerate the high temperature is

used to promote the crystallization process, but it must be chemically swapped afterward for a

different compound that makes the material water soluble. The ligand exchange stepas well as

several variations on the processis known to significantly alter the luminescence and stability

of the resulting quantum dots.

Biomedical applications require high-quality water-soluble quantum dots. Quantum dots could

be made directly in water but often have narrow available size ranges and wide size distribution.

On the contrary, quantum dots produced from high temperature organic solvent synthetic

strategies are monodisperse (leads to narrow FWHM) with very wide emission color ranging

from ultraviolet to near infrared (3002500 nm) by simply changing the size, composition and/or

structure. However, these quantum dots synthesized in organic solvents are insoluble in water.

William W. Yu et al. [30] has given a method to make the high-quality hydrophobic quantum

dots soluble in water and also active in bioconjugate reactions.

The quantum dots synthesized in organic solvents have hydrophobic surface ligands such as

trioctylphosphine oxide (TOPO), trioctylphosphine (TOP), tetradecylphosphonic acid (TDPA) or

oleic acid. These hydrophobic ligands could be replaced by some water-soluble bifunctional


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molecules in which one end connects to quantum dot surface atoms and the other end is

hydrophilic and may also be reactive to biomolecules (Fig. 5.5). Examples of some water-soluble

bifunctional molecules used are mercaptocarbonic acids [HS-(CH2)n-COOH, n = 115], 2-

aminoethanethiol, dithiothreitol, dihydrolipoic acid, oligomeric phosphines, peptides, and cross-

linked dendrons.

Figure 5.5. Quantum dot (QD) water solubilization strategies.

At the same time they found that quantum dots could enter the cells through endocytosis, and the

cell death was highly related to the uptake quantity no matter what surface coating is.

Nonetheless, the surface coating did affect the uptake quantity and in turn influenced the

intracellular cytotoxicity [31].


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Figure 5.6. In vitro cytotoxicity of water-soluble quantum dots with different PEG coatings (the

numbers of 750 and 6000 are the molecular weights of PEG polymers) to SK-BR-3 human breast

cells. Full growth medium of confluent SK-BR-3 cells were incubated with water-soluble

quantum dots in the dark over 24 h.

6. Nanomaterials in Biomedical Applications:

Application of nanomaterials in biomedical sectors can be divided into various areas, such as

Drug delivery, disease detection, Tissue Engineering, biosensor, MRI contrast enhancement,

antimicrobial treatment, protein detection, Manipulation of cells and biomolecules, Cancer and

tumor therapy, etc.

We will discuss some of the areas where nanomaterials are indispensable.

6.1 Drug Delivery:

Drug delivery systems (DDSs) provide positive attributes to a free drug by improving

solubility, in vivo stability, and biodistribution. They can also alter unfavorable

pharmacokinetics of some free drugs. Moreover, huge loading of pharmaceuticals on DDSs can

render drug reservoirs for controlled and sustained release to maintain the drug level within


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therapeutic window. For example, a gold nanoparticle with 2 nm core diameter could be, in

principle, conjugated with ~100 molecules to available ligands (n=~108) in the monolayer [14].

Zubarev et al. have recently succeeded in coupling of ~70 molecules of paclitaxel, a

chemotherapeutic drug, to a GNP with 2 nm core diameter [32].

Drug delivery and related pharmaceutical development in the context of nanomedicine should beviewed as science and technology of nanometer scale complex systems (101000 nm), consisting

of at least two components, one of which is a pharmaceutically active ingredient, although

nanoparticle formulations of the drug itself are also possible. The whole system leads to a special

function related to treating, preventing or diagnosing diseases sometimes called smart-drugs or

theragnostics. The primary goals for research of nano-bio-technologies in drug delivery include:

More specific drug targeting and delivery, Reduction in toxicity while maintaining therapeutic effects, Greater safety and biocompatibility, and Faster development of new safe medicines [33].

The main issues in the search for appropriate carriers as drug delivery systems pertain to the

following topics that are basic prerequisites for design of new materials. They comprise

knowledge on (i) drug incorporation and release, (ii) formulation stability and shelf life (iii)

biocompatibility, (iv) biodistribution and targeting and (v) functionality. In addition, when used

solely as carrier the possible adverse effects of residual material after the drug delivery should be

considered as well.

One of the major challenges in drug delivery is to get the drug at the place it is needed in the

body thereby avoiding potential side effects to non diseased organs. This is especially

challenging in cancer treatment where the tumor may be localized as distinct metastases in

various organs. The non restricted (cyto) toxicity of chemotherapeutics thus limits the full use of

their therapeutic potential. Local drug delivery or drug targeting results in increased local drug

concentrations and provides strategies for more specific therapy. Nanoparticles have specific

particles as tools to enable these strategies. These include benefits such as their small size which

allows penetration of cell membranes, binding and stabilization of proteins, and lysosomal

escape after endocytosis.


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Ajay kumar gupta et al [34]. has shown that paramagnetic nanoparticles are also important for

drug delivery.

Recent work by Kannan and Katti et al [35]. investigated gum arabic labeled radioactive AuNPs

that localize in liver. This study combines the therapeutic property of radioactive gold 198Au

(max = 0.96 MeV, t1/2 = 2.7 days) and target specific biomolecule to form a powerful

radiopharmaceutical for targeted drug delivery. This gum Arabic labeled radioactive gold can be

used to treat liver cancers with higher radiation dose inherent to radioactive nanoparticles that

contain thousands of radioactive atoms. Patri AK et al. has shown that drug delivery can be

proceeding by dendrimers also [36].

Barrett E. Rabinow [37] has shown a drug delivery system by nanoparticles in the figure 6.1 a

and 6.1 b below:


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Figure 6.1 a. Trafficking of drug nanoparticles by macrophages, monocytes and

neutrophils.

Tao Xu et al. [38] explained solid nanoparticles, polymeric nanoparticles, and polymeric

selfassemblies, have attracted increasing attention for use as potential drug delivery systems. The


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advantages of using nanoparticle systems for drug delivery result from their two basic properties.

First, nanoparticulates, due to their small size, can penetrate small capillaries and be taken up by

cells, which allows for efficient drug accumulation at target sites in the body. Second, the use of

biodegradable materials for nanoparticulate preparation allows for sustained drug release within

the target over a period of days or even weeks after administration.

Figure 6.1 b. schematic illustration of drug delivery via active and

passive targeting, solid and dotted line respectively.

Gold nanoparticles are capable of delivering large biomolecules, without restricting themselves

as carriers of only small molecular drugs. Tunable size and functionality make them a useful

scaffold for efficient recognition and delivery of biomolecules. They have shown the success in


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delivery of peptides, proteins, or nucleic acids like DNA or RNA. Gold nanoparticles can

likewise be nanocarriers of peptides and proteins of interest. Rotello et al. have reported that

cationic tetraalkyl ammonium functionalized GNPs recognize the surface of an anionic protein

through complementary electrostatic interaction and inhibit its activity (Fig. 6.2) [14]. The

activity was recovered due to release of free protein by treating the proteinparticle complexwith GSH, showing GNPs as potential protein transporters.

Figure 6.2. Schematic representation of glutathione (GSH)-mediated disruption

of nanoparticle -galactosidase protein interactions.

Gold Nanoparticles provide attractive candidates for gene delivery. They can be made quite

small to provide a high surface-to-volume ratio, maximizing the payload/carrier ratio. Perhaps

equally important, the monolayer coverage of MPCs and MMPCs systems allow tuning of the

charge and hydrophobicity to maximize transfection efficiency while minimizing toxicity. We

have shown in our earlier studies that gold nanoparticles functionalized with cationic quaternary

ammonium groups (a) bind plasmid DNA through electrostatic interactions.

Many researcher reveals that gold nanoparticles have good drug delivery capability.

Nevertheless, dendrimers are also very efficient for drug delivery point of view. Sonke Svenson


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[39] has shown how drug delivery takes place by with the help of dendrimer nanoparticles. He

also reviewed the bio compatability of the dendrimers. The therapeutic areas for dendrimerdrug

formulations include anticancer, anti-inflammatory, and antimicrobial treatments. In many cases,

dendrimers have been functionalized with poly(ethylene glycol) (PEG) chains in order to

enhance their container properties and to improve the biocompatibility of these carriermolecules.

Figure 6.3. Mechanism of dimeric prodrug activation by a single enzymatic cleavage [40]

The biocompatibility of dendrimers follows patterns known from other small particles such as

micelles and liposomes. Cationic surfaces show cytotoxicity; however, derivatization with fatty

acid or PEG chains, reducing the overall charge density and minimizing contact between cell

surfaces and dendrimers, reduces these toxic effects [38]. In the figure 6.4 represents the

dendritic structure and the effect of PEG.


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Figure6.4. (A) Structure of a poly(etherhydroxylamine) (PEHAM) dendrimer G1 conjugatedwith 25% of PEG550 to its surface. (B) Solubility enhancement of camptothecin formulated with

PEHAM dendrimer G1-PEG550 in water (light) and wateralcohol (dark) compared to drug as

received. (C) Dissolution curves of free drug and lyophilized drug formulations with PEHAM

dendrimers G1-PEG550 (2) and G3-OH (3) [41].


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6.2 Disease detection:

A number of researchers discovered that a nanoparticle has disease detection capability in human

body. For disease detection different nanomaterials are being used. Such as cancer cell

detectionat early stages, tumor detection as well as treatment, bacterial protein detection and

destruction, etc.

Optical and electronic properties of AuNPs can be utilized to enhance the contrast in molecular

imaging for the detection of cancer at early stages. For example, AuNPs labeled with monoclonal

antibodies against EGFR (epidermal growth factor receptor) that are over-expressed in skin

cancer were shown to localize on the abnormal cervical SiHa cell lines by imaging via ndoscope-

compatible microscopies, such as optical coherence tomography and reflectance confocal

microscopy [42].

Kenneth E. Scarberry et al. [43] says in their one research paper that Magnetic cobalt spinel

ferrite nanoparticles coated with biocompatible polygalacturonic acid were functionalized with

ligands specific for targeting expressed EphA2 receptors on ovarian cancer cells. By using such

magnetic nanoparticle-peptide conjugates, targeting and extraction of malignant cells were

achieved with a magnetic field. Targeting ovarian cancer cells with receptor specific peptide-

modified magnetic nanoparticles resulted in cell capture from a flow stream in vitro and from the

peritoneal cavity of mice in vivo. Successful removal of metastatic cancer cells from the

abdominal cavity and circulation using magnetic nanoparticle conjugates indicate the feasibility

of a dialysis-like treatment and may improve long term survival rates of ovarian cancer patients.

This approach can be applied for fighting other cancers, such as leukemia, once the receptors on

malignant cells are identified and the efficacy of targeting ligands is established.

Apart from that Magnetic iron oxide nanoparticles encased in a biocompatible material can make

detecting cancer cells easier, even if the cancer cells are small and clearer so there is less

mistakes in the detecting process. These particles stick to the tumor cells turning them into little

magnets which are then attracted to the tip of a biopsy needle [44].


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6.3 Tissue Engineering:

As emerging areas, tissue and implant engineering are evolving to address the shortage of human

tissue and organs. The core of the tissue engineering and regenerative medicine are the

fabrication of scaffolds, in which a given cell population is seeded, proliferated, and

differentiated with the introduction of functional cell types from many different sources [45].

Nanostructured materials and their modified forms offer some attractive possibilities in the fields

of tissue and implant engineering [34]. Bone-like nanostructure scaffolds have been developed

using the technology of composites to imitate natural bone in bone tissue engineering [46].

Magnetic nanoparticles have been used in cell isolation and purification for tissue engineering

and other applications. Nanoparticles can be conjugated with intense, stable fluorescence for

tracing cells through several generations, which is ideal for the study of migration, motility,

morphology and other cell functions.

Figure 6.5. (A) Schematic drawing of long bone microstructure (compact bone). (BD)Schematic drawing of honeycomb scaffold for guided and biomimetic long bone tissue

regeneration. (E) nano-hydroxyapatite (NanoHA)- and degradable polymer based honeycomb

scaffold. (F) A honeycomb scaffold was implanted into radius defect rabbits to regenerate longbone.


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Biomimetic processing is based on the idea that biological systems store and process information

at the molecular level. Extending this concept to the processing of nanocomposites for

biomedical devices and tissue engineering, such as scaffold for bone regeneration, has been

brought out in the last few years [46]. Several research groups have reported the synthesis of

novel bone nanocomposites of HA and collagen, gelatin, or chondroitin sulfate, through a self-assembly mechanism. Indeed, hierarchical self-assembly of nano-fibrils is ubiquitous in nature,

as in bone, muscle, and intestine, etc, and can lead to the creation of specific shapes and

conformations in macromolecular structures. The mechanical property of CNT polystyrene

composite is increased through covalent crosslinkage between CNTs and polymer matrix (fig.

6.6) [37].

Figure 6.6. High-resolution-TEM showing the ultra-thin (2 nm) coating on CNT (A)

increased the tensile strength of the CNT-polystyrene composite.


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6.4 Diagnosis and treatment:

The biological application of nanoparticles is a rapidly developing area of nanotechnology that

raises new possibilities in the diagnosis and treatment of human cancers. In cancer diagnostics,

fluorescent nanoparticles can be used for multiplex simultaneous profiling of tumor biomarkers

and for detection of multiple genes and matrix RNA with fluorescent in-situ hybridisation.

Maksym V Yezhelyev et al. [47] says that some breast cancers express protein biomarkers (eg:

oestrogen receptor, progesterone receptor, and ERBB2) on which therapeutic decisions are made.

Semiconductor fluorescent nanocrystals, such as quantum dots, have been conjugated to

antibodies, allowing for simultaneous labelling and accurate quantification of these target

proteins in one breast tumour section. The use of nanoparticlesnot only quantum dots of

different sizes and emission spectra, but also gold-containing nanoparticles (i.e., Raman

probes)will allow the simultaneous detection and quantification of several proteins on small

tumour samples, which will ultimately allow the tailoring of specific anticancer treatment to an

individual patients specific tumor protein profile.

The ability to detect molecular targets simultaneously on individual tumor samples could allow

correlation between gene products and proteins in real time. In addition, the effects of an

individual treatment on expression of the target protein can be monitored before and after

treatment, and provide a rapid method to measure the efficacy of a targeted therapy [48].

As earlier we have discussed, Quantum dots are fluorescent nanoparticles with sizes of 210 nm

that contain a core of hundreds to thousands of atoms of group II and VI elements (e.g.,

cadmium, technetium, zinc, and selenide) or group III (e.g., tantalum) and V elements (e.g.,

indium).22,23 Quantum dots containing a cadmium selenide core and a zinc sulphide shell,

surrounded by a coating of a coordinating ligand and an amphiphilic polymer, are most

commonly used for biological application. This structure enables quantum dots to emit powerful

fluorescence that differs in nature from organic dyes. Quantum dots can be tuned to emit waves

at between 450 nm and 850 nm (i.e., from ultraviolet to near infrared) by changing the size or

chemical composition of the nanoparticle [47]. This so-called quantum confinement effect

produces many quantum-dot colours, which can be visualized simultaneously with one light

source. Quantum dots emit narrow symmetrical emission peaks with minimum overlap between

spectra, allowing unique resolution of their spectra and measurement of fluorescent intensity

from several multicolour fluorophores by real-time quantitative spectroscopy. These key

advantages make it possible to label multiple molecular targets simultaneously by use of


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quantum dots both in vitro and in vivo. However, use of quantum dots in imaging and

therapeutics in vivo is limited by the toxic effects of the heavy-metal core (fig. 6.7).

Figure 6.7. Methods for conjugating quantum dots to biomolecules EDAC=ethyl-3-dimethyl-amino-propyl-carbodiimide. SMCC=succinimidyl-4-N-maleimidomethyl-cyclohexane

carboxylate. COOH=carboxyl group. NH2= amine group. SH=sulohydryl group. (A) Traditional

covalent crosslinking chemistry with EDAC as catalyst. (B) Conjugation of antibody fragmentsto quantum dots via reduced sulphhydrylamine coupling.

The level of fluorescent emission from these conjugated nanoparticles correlates with expression

of the protein (fig.6.8). The bright fluorescence of quantum dots enables identification of targetsin low levels in cancer cells, resulting in increased sensitivity [49].


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Figure 6.8: Use of quantum dots to detect protein expression in tumour expressing oestrogen

receptor and progesterone receptor (top) or ERBB2 (bottom) (A) Paraffin-embedded human

breast tumours stained with human antibodies against oestrogen receptor (ER), ERBB2, andprogesterone receptor (PR) conjugated with quantum dots (565 nm, 655 nm, and 605 nm,

respectively). (B) Fluorescent intensity from quantum dots shows level of labelled biomarker

expression in each tumour. au=arbitrary units.

Alf Lamprecht et al [50]. has shown how the nanoparticles acts to delivers the drug and at the

same time how does it acts to treatment of inflammatory Bowel disease.

All nanoparticles were prepared with poly[DL-lactide-coglycolide], a biocompatible and

biodegradable polymer that is now well established for use in humans. Nanoparticles were

characterized in terms of size, polydispersity, surface potential, encapsulation efficiency, and

drug release. The biodegradable polymer poly[DL-lactide-co-glycolide] 50/50 (PLGA) (mol. wt.5,000 or 20,000) was purchased from Wako (Osaka, Japan). Rolipram was received as a gift

from Schering AG (Berlin, Germany). Trinitrobenzenesulfonic acid (TNBS) and o-dianisidine

hydrochloride were obtained from Sigma Chemical (Deisenhofen, Germany) and

hexadecyltrimethylammonium bromide was obtained from Fluka (Deisenhofen, Germany). All


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other chemical reagents were purchased from Sigma Chemical (Steinheim, Germany), Merck

AG (Darmstadt, Germany), or Nacalai Tesque Inc. (Kyoto, Japan) and were of analytical grade.

To evaluate the therapeutic value of rolipram-containing nanoparticles, the effect of the carrier

system was studied on preexisting colitis. On day 3, all animals received an intrarectal

application of TNBS except the healthy control group. Before this time point, animals showed noclinical problems. After inducing the experimental colitis the clinical score increased rapidly and

consistently for the next 3 days for all groups. The inflamed tissue showed an extremely

increased mucus production in the area of distal colon compared with the histology of healthy

gut sections from the control group (fig. 6.9). Significant damages of the intestinal tissue, e.g.,

ulceration, have been observed [51].

Figure 6.9. Determination of colon/body ratio (a) and myeloperoxidase activity (b) after final

drug administration (day 11) and washout phase (day 15). Healthy control group ( ), colitiscontrol group (t), rolipram solution receiving group (s), PLGA nanoparticles (mol. wt. 20,000)-

receiving group (p), and PLGA nanoparticles (mol. wt. 5,000)-receiving group (o).

From the above discussion we have seen that the disease detection and treatment according to the

degree of inflammation of the disease, different nanomaterials can be used. Fortunately it is

revealed that the efficiency for the purposes of treatment of the disease nanomaterials areindispensable for the advance generation of human being.


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7. Conclusion:

Nanotechnology is a very vast area. In this review it is not possible to elaborate all the aspects of

a big technology. Some of the important points have been discussed in this space.

As we know that nanotechnology is the understanding and control of matter at dimensions of

roughly 1 to 100 nanometers, where unique phenomena enable novel applications. A nanometer

is one billionth of a mater (10-9

m).

These very small materials have typical characteristics. With the help of those characteristics

nanomaterials are being used in biomedical sectors. Huge applications of nanomaterials have

been takes place in that sector due to its different merits to different acts. Some of the

applications in biomedical have been enlisted which are overviewed in this occasion.

Here we have discussed about

Types of nanomaterialsCarbon Based Materials

Metal Based Materials

Dendrimers

Nanocomposites

Different Nanostructures Synthesis of the nanomaterials Importance of nanomaterials Activities of the nanomaterials Application of the nanomaterials in different biomedical sectors

Such as:

Drug Delivery

Disease detection

Tissue Engineering

Diagnosis and treatmentFor those applications different types of nanomaterials are being used, such as,

Gold/Silver nanoparticles, carbon nanotubes, quantum dots, dendrimers, metallic

magnetic nanoparticles and different metal oxide etc.


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An Overview on Nano Materials for Bio Medical Application