1. Introduction

A growing interest in the medical applications of nanotechnology has led to the emergence of a

new field called nanomedicine (Saha, 2009). Nanomedicine offers the prospect of powerful new

tools for the treatment of human diseases and the improvement of human biological systems

using molecular nanotechnology. Nanotechnology, ‘the manufacturing technology of the 21st

century’, will provide an opportunity to build a broad range of economically complex molecular

machines (including, not incidentally, molecular computers). It will lead to the building of

computer controlled molecular tools much smaller than a human cell with the accuracy and

precision of drug molecules. Such tools will allow medicine, for the first time to intervene in a

sophisticated and controlled way at the cellular and molecular level (Ralph, 1996). They could

remove obstructions in the circulatory system, kill cancer cells, or take over the function of sub

cellular organelles. Just as today the artificial heart has been developed, so in the future, perhaps

artificial mitochondrion would be developed (Ralph, 1996).

The ultimate goal of nano medicine is to improve the quality of life. Broadly the aim of nano

medicine may is the comprehensive monitoring, repairing and improvement of all human

biological systems, working from the molecular level using engineered devices and

nanostructures to achieve medical benefit. Taken together, nanomedicine is the process of

diagnosing, treating, and preventing disease and traumatic injury, relieving pain, and of

preserving and improving human health, using molecular tools and molecular knowledge of the

human body (Freitas, 2002).

However, nano materials are now being designed to aid the transport of diagnostic or therapeutic

agents through biologic barriers; to gain access to molecules; to mediate molecular interactions;

and to detect molecular changes in a sensitive, high through put manner. In contrast to atoms and

macroscopic materials, nano materials have a high ratio of surface area to volume as well as

tunable optical, electronic, magnetic, and biologic properties, and they can be engineered to have

different sizes, shapes, chemical compositions, surface chemical characteristics, and hollow or

solid structures (Xia et al., 2009; Peer et al., 2007).

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2. Defination

2.1. Defination of Nanotechnology

Nanotechnology is the development and use of techniques to study physical phenomena and

construct structures in the physical size range of 1-100 nanometers (nm), as well as the

incorporation of these structures into applications ( Kostoff et al., 2007).

It can be defined as the “intentional design, characterization, production,and applications of

materials, structures, devices, and systems by controlling their size and shape in the nanoscale

range (1 to 100 nm).” (Kim et al., 2010). In other sense it can simply be defined as the

technology at the scale of one-billionth of a metre. It is the design, characterization, synthesis

and application of materials, structures, devices and systems by controlling shape and size at

nanometer scale (Stylios et al., 2005). It is the ability to work at the atomic, molecular and

supramolecular levels to create and employ materials, structures, devices and systems with

basically new properties (Roco, 2003). Scientifically, nanotechnology is employed to describe

materials, devices and systems with structures and components exhibiting new and significantly

improved physical, chemical and biological propertiesas well as the phenomena and processes

enabled by the ability to control properties at nanoscale (Miyazaki and Islam, 2007).

Materials exhibit unique properties at nanoscale of 1 to 100 nanometre (nm). The changes in

properties are due to increase in surface area and dominance of quantumeffects which is

associated with very small sizes and large surface area to volume ratio (Williams, 2008). The

quantum effects at nanoscale determine a material’s magnetic, thermal, optical and electrical

properties. It is expected generally,that products at nanoscale will be cheaper due to less quantity

of materials utilized.

2.2. Defination of Nanomedicine

Nanomedicine is the application of nano technology to medicine. It is the preservation and

improvement of human health, using molecular tools and molecular knowledge of the human

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body. Present day nanomedicine exploits carefully structured nanoparticles such as dendrimer,

carbon fullerenes and nanoshells (Mashino T et al., 2005) to target specific tissue and organs.

These nanoparticles may serve as diagnostic and therapeutic antiviral, antitumor or anti cancer

agents. But as this technology mature in the year ahead, complex nanodevices and even

nanorobots will be farbricated, first of biological material but later using more durable materials

such as diamond to achieve the most powerful result. (Freitas jr RA, 2000)

3. Application in medicine and health care /Diseases and Cures by Nanomedicine

Medical science has scored some impressive successes. Antibiotics have reduced diseases caused

by bacteria remarkably. Nowadays, vitamin and mineral deficiency diseases are rare in

developed nations. However, there are still many diseases that limit our lifespan, and the

medicines concerned can only postpone them but are not able to cure. Life cannot be extended

indefinitely without curing each disease that threatens to shorten it.

The application of nanotechnology to the medical sector is referred to as Nanomedicine.

Specifically, this area of application uses nanometre scale materials and nano-eneabled

techniques to diagnosis, monitor, treat and prevent diseases. These include cardiovascular

diseases, cancer, musculoskeletal and inflammatory conditions, neurodegenerative and

psychiatric diseases, diabetes and infectious diseases (bacterial and viral infections, such as

HIV). The potential contribution of nanotechnology in the medical sector is extremely broad and

includes new diagnostic tools, imaging agents and methods, drug delivery systems and

pharmaceuticals, therapies, implants and tissue engineered constructs (Kubik et al., 2005).

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Table 1: Application of Nanomedicine for the Healthcare (Bharali et al., 2009; Park, 2002;

Thorek et al., 2006; Partha and Conyers, 2009; Stya and Srinivasa, 2006; Hirsch et al., 2006)

3.1 Treatment of Cancer

Today’s monoclonal antibodies are able to bind to only a single type of protein or other antigen,

and not proved effective against most cancers. The cancer-killing device mentioned here could

incorporate a dozen different binding sites and so could monitor the concentrations of a dozen

different types of molecules. The computer could determine if the profile of concentrations fit a

pre-programmed “cancerous” profile and would, when a cancerous profile was encountered,

release the poison (Ralph, 1996; Saha, 2009)

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3.2 Prevention of Brain Damage in Neurodegenerative Diseases

Damaged neurons, like other cells, sometimes go into suicide mode (called “apoptosis”); this can

be chemically prevented, and the neuron can be stabilized until the problem is fixed and the

damage is repaired. It is now acknowledged that brain cells do regenerate; the brain is generating

new cells all the time. This implies that some neural death is normal. It seems that a new neuron

can take its cues from the existing ones; this means that a person’s mind may be intact even after

the death and replacement of a large percentage of their neurons. Finally, it may be possible to

measure neural connections and/or activity in enough detail to simulate the firing pattern. This

may make it possible to create an artificial neuron or even an artificial neural net that can be used

to replace missing neurons and retain old memories. But even if this proves to be impossible, the

worst-case scenario is one in which people cannot remember much farther than a century back.

More memory loss than this can be accepted as a natural consequence of aging (Saha, 2009)

3.3 Hormone Deficiency

Aging is associated with changes in the levels of many hormones; perhaps the best known

example is menopause, which is caused by a reduction in estrogen. It is likely that treating glands

against aging at the cellular level would restore age-appropriate hormone production. However,

if this is not enough to bring the body to a younger state, artificial glands could be built that

would maintain the desired hormone levels. In fact, different hormone levels could be supplied to

different organs -something that the body cannot do for itself. This would be an example of

heterostasis (Saha, 2009).

3.4 For the treatment of Infection

With great effort, we managed to eradicate smallpox using 1970’s technology. Cheap

manufacturing would allow the creation of billions of doses of highly effective treatments that

would be easy to distribute and administer; the main obstacles to wiping out many diseases

worldwide would be political, not economic or technological. Nanorobotic ‘Microbivores’ the

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nanorobotic phagocytes (artificial white cells) traveling in the bloodstream could be 1000 times

faster-acting than white blood cells and eradicate 1000 times more bacteria, offering a complete

antimicrobial therapy without increasing the risk of sepsis or septic shock (as in traditional

antibiotic regimens) and without the release of biologically active effluents. Microbivores could

also be useful for treating infections of the meninges or the cerebrospinal fluid (CSF) and

respiratory diseases involving the presence of bacteria in the lungs or sputum, and could also

digest bacterial biofilms. These handy nanorobots could quickly rid the blood of nonbacterial

pathogens such as viruses (viremia), fungus cells (fungemia), or parasites (parasitemia). Outside

the body, microbivore derivatives could help clean up biohazards, toxic biochemicals or other

environmental organic materials spills, as in bioremediation (Saha, 2009).

3.5 For Life Saving after Accidents

Primary medical applications of respirocytes would include transfusable blood substitution;

partial treatment for anemia, perinatal/neonatal, and lung disorders; enhancement of

cardiovascular/neurovascular procedures, tumor therapies and diagnostics; prevention of

asphyxia; artificial breathing; and a variety of sports, veterinary, battlefield, and other uses. The

clottocytes are artificial platelets that could stop human bleeding within ~1 second of physical

injury, but using only 0.01% the bloodstream concentration of natural platelets. In other words,

nanorobotic clottocytes would be around 10,000 times more effective as clotting agents than an

equal volume of natural platelets. Nanorobotic artificial mechanical platelets (Clottocytes) could

allow for complete hemostasis in as little as one second - 100 to 1000 times faster than the

natural system. They could also work internally. Using acoustic pulses, a blood vessel break

could be rapidly communicated to neighboring clottocytes, immediately triggering a progressive

controlled mesh-release cascade (Freitas, 1998).

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3.6 Diagnostic Imaging

Techniques such as X-ray, computer tomography (CT), ultrasound (US), magnetic resonance

imaging (MRI) and nuclear medicine (NM) are well established imaging techniques, widely used

both in medicine and biochemical research. Originally, imaging techniques could only detect

changes in the appearance of a tissue when the symptoms of the disease were relatively

advanced. Later, targeting and contrast agents were introduced to mark the disease site at the

tissue level, increasing imaging specificity and resolution. It is in this specific area that

nanotechnology is making its highest contribution by developing better contrast agents for nearly

all imaging techniques. The physiochemical characteristics of the nanoparticles (particle size,

surface charge, surface coating and stability) allow the redirection and the concentration of the

marker at the site of interest. An example of nanoparticles used in research for imaging are

perfluorocarbon nanoparticles employed as contrast agents for nuclear imaging, magnetic

resonance imaging and ultrasound, with application to the imaging of blood clots, angiogenesis,

cancer metastases and other pathogenic changes in blood vessels. Gadolium complexes have

been incorporated into emulsion nanoparticles for the molecular imaging of thrombus resulting

in a dramatic enhancement of the signal compared to usual MRI contrast agents (Flacke et al.,

2001).

Figure 1. Low-resolution images (3D GraSE) of fibrin clots targeted with nanoparticles

presenting a homogeneous, T1-weighted enhancement that improves with increasing gadolinium

level (0, 2.5, and 20 mol%). (Flacke et al., 2001).

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4. Nanotechnology and medical applications:

4.1 Liposomes

Liposomes were first developed about 40 years ago. They are small artificial vesicles(50 –

100nm) developed from phospholipids such as phosphatidylcholine,

phosphatidylglycerol,phosphatidylethanolamine and phosphatidylserine, which have been used

in biology, biochemistry, medicine, food and cosmetics( Shafirovich et al., 2007; Patel-Predd ,

2008;Hu et al., 2003;Heron et al., 2007).The characteristics of liposomes are determined by the

choice of lipid, their composition, method of preparation, size and surface charge(Stylios et al.,

2005). Liposomes have been applied as drug carriers due to their ability to prevent degradation

of drugs, reduce side effects and target drugs to site of action (Cortie, 2004). However,limitations

of liposomes include low encapsulation efficiency, rapid leakage of water-soluble drug in the

presence of blood components and poor storage stability (Cortie , 2004;Cortie and van der

Lingen , 2002). However, surface modification may confer stability and structure integrity

against harsh bio-environment after oral or parenteral administration (Overbury, 2005). Surface

modification can be achieved by attaching polymers such as poly (methacrylic acid-co-stearyl

methacrylate) and polyethylene glycol units to improve the circulation time of liposomes in the

blood; and by conjugation to antibodies or ligands such as lectins for target specific drug

delivery and stability (Cortie and van der Lingen , 2002; Overbury , 2005; Jain et al., 2008).

Applications of liposomes include transdermal drug delivery to enhance skin permeation of

drugs with high molecular weight and poor water solubility (Roco , 1999); a carrier for delivery

of drugs, such as gentamicin, in order to reduce toxicity( Yin , 2007); possible drug delivery to

the lungs by nebulisation(Eijkel and van den Berg , 2006); ocular drug delivery ( Sheeparamatti

et al.,2007) and in the treatment of parasitic infections. However, solid lipid nanoparticles

(SLNs) provide an effective alternative due to their stability, ease of scalability and

commercialisability (Smith, 2006).

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Other vesicular structures include transferosomes, ethosomes, niosomes and marinosomes which

are used mainly for transdermal delivery (Shafirovich et al., 2007; Ball , 2005;Bittner , 2005).

Figure 2: Liposome for drug delivery (Smith, 2006).

Liposomes discovered in mid 1960s were the original models of nanoscaled drug delivery

devices.They are spherical nanoparticles made of lipid bilayer membranes with an aqueous

interior but can be unilamellar with a single lamella of membrane or multilamellar with multiple

membranes. They can be used as effective drug delivery systems. Cancer chemotherapeutic

drugs and other toxic drugs like amphotericin and hamycin, when used as liposomal drugs

produce much better efficacy and safety as compared to conventional preparations. These

liposomes can be loaded with drugs either in the aqueous compartment or in the lipid membrane.

Usually water soluble drugs are loaded in aqueous compartment and lipid soluble drugs are

incorporated in the liposomal membrane (Gregoriadis and Ryman, 1972). The major limitation

of liposome is its rapid degradation and clearance by the liver macrophages (McCormack and

Gregoriadis, 1994),

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thus reducing the duration of action of the drug it carries. This can be reduced to a certain extent

with the advent of stealth liposomes where the liposomes are coated with materials like

polyoxyethylene (Illum and Davis, 1984) which prevents opsonisation of the liposome and their

uptake by macrophages (Senior et al., 1991). Other ways of prolonging the circulation time of

liposomes are incorporation of substances like cholesterol (Kirby and Gregoriadis, 1983),

polyvinylpyrollidone polyacrylamide lipids (Torchilin et al., 1994) and high transition

temperature phospholipids distearoyl phosphatidylcholine (Forssen et al., 1992).

4.1.1 Targeting of liposomal drugs

Immunoliposomes are liposomes conjugated with an antibody directed towards the tumour

antigen. These immunoliposomes when injected into the body, reaches the target tissue and gets

accumulated in its site of action. This reduces unwanted effects and also increases the drug

delivery to the target tissue, thus enhancing its safety and efficacy (Surendiran et al., 2009).

The targeted liposomal preparations are found to have a better efficacy than non targeted

liposomes.

4.2 Nanopores

Nanopores designed in 1997 by Desai and Ferrari (Desai et al., 1998), consist of wafers with

high density of pores (20 nm in diameter). The pores allow entry of oxygen, glucose and other

products like insulin to pass through. However, it does not allow immunoglobulin and cells to

pass through them. Nanopores can be used as devices to protect transplanted tissues from the

host immune system, at the same time, utilizing the benefit of transplantation. β cells of pancreas

can be enclosed within the nanopore device and implanted in the recipient’s body. This tissue

sample receives the nutrients from the surrounding tissues and at the same time remains

undetected by the immune system and hence do not get rejected. This could serve as a newer

modality of treatment for insulin dependent diabetes mellitus (Leoni and Desai, 2001).

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Nanopores can also be employed in DNA sequencing. Nanopores are also being developed with

ability to differentiate purines from pyrimidines. Further, incorporation of electricity conducting

electrodes is being designed to improve longitudinal resolution for base pair identification

( Freitas , 2005).Such a method could possibly read a thousand bases per second per pore. These

can be used for low cost high throughput genome sequencing (Deamer and Akeson , 2000)which

would be of great benefit for application of pharmacogenomics in drug development process.

4.3 Fullerenes

Fullerenes, a carbon allotrope, also called as “bucky balls” were discovered in 1985 (Thakral and

Mehta, 2006).The buckminster fullerene is the most common form of fullerene measuring about

7 A in diameter with 60 carbon atoms arranged in a shape known as truncated icosahedrons

(Kratschmer et al., 1990). It resembles a soccer ball with 20 hexagons and 12 pentagons and is

highly symmetrical (Taylor et al., 1990).

4.3.1 Types of fullerenes

Alkali doped fullerenes are structures with alkali metal atoms in between fullerenes

Contributing valence electrons to neighbouring fullerenes (Chandrakumar and Ghosh ,

2008).They occur because of the electronegative nature of the fullerenes.

Endohedral fullerenes have another atom enclosed inside the buckyball. If a metallic atom is

enclosed,these are called as metallofullerenes ( Fatouros et al., 2006; Komatsu et al., 2005).

Due to the small size of C60 fullerene, it is difficult to synthesize endohedral C60 fullerenes.

However, larger fullerenes such as C82 or C84 fullerenes are used for synthesizing endohedral

fullerenes. Endohedral metallofullerenes can be used for diagnostic purposes as radio contrast

media in magnetic resonance imaging and other imaging procedures. Since the radioactive metal

is enclosed within the buckyball, these are less toxic and safer. This method can also be

employed for imaging organs as radioactive tracers (Komatsu et al., 2005).

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Exohedral fullerenes also called as fullerene derivatives are synthesized by chemical reaction

between the fullerene and other chemical groups.

These are also called as functionalized fullerenes. Such fullerenes can be used as photosensitizers

in photodynamic therapy for malignancies. These generate reactive oxygen species when

stimulated by light and kills the target cells. This method is now also being investigated for

antimicrobial property as these cause cell membrane disruption especially in Gram positive

bacteria and mycobacterium (Mroz et al., 2007; Tegos et al., 2005; Bosi et al., 2000).

Heterofullerenes are fullerene compounds where one or more carbon atoms are replaced by other

atoms like nitrogen or boron (Thakral and Mehta, 2006).

Fullerenes are being investigated for drug transport of antiviral drugs, antibiotics and anticancer

agents (Mroz et al., 2007; Tegos et al., 2005; Bosi et al., 2000; Ji et al., 2008).

Fullerenes can also be used as free radical scavengers due to presence of high number of

conjugated double bonds in the core structure. These are found to have a protective activity

against mitochondrial injury induced by free radicals (Cai et al., 2008).

However, fullerenes can also generate reactive oxygen species during photosensitization. This

property can be used in cancer therapy (Markovic and Trajkovic, 2008).

Fullerenes have the potential to stimulate host immune response and production of fullerene

specific antibodies. Animal studies with C60 fullerene conjugated with thyroglobulin have

produced a C60 specific immunological response which can be detected by ELISA with IgG

specific antibodies. This can be used to design methods of estimation of fullerene levels in the

body when used for therapeutic or diagnostic purposes (Chen et al., 1998).On intravenous

injection, these get distributed to various parts of the body and get excreted unchanged through

the kidney. Soluble derivates of fullerenes are more biocompatible compared to insoluble forms

of fullerenes and have low toxic potential even at higher doses (Chen et al., 1998). Further, the

degree of purification of fullerene determines its cost and highly purified fullerenes are

expensive, restricting its application in medical field (Thakral and Mehta, 2006).

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4.4 Biosensors

A sensor is a device capable of recognizing a specific chemical species and ‘signalling’ the

presence, activity or concentration of that species in solution through some chemical change. A

‘transducer’ converts the chemical signal (such as a catalytic activity of a specific biomolecule)

into a quantifiable signal (such as a change in colour or intensity) with a defined sensitivity.

When the sensing is based on biomolecular recognition it is called a biosensor. There are various

types of biosensors, such as antibody/antigen based, nucleic acid based and enzyme based. Also,

depending on the technique used in signal transduction, biosensors are classified as optical-

detection biosensors (as in the example above), electrochemical biosensors, mass-sensitive

biosensors and thermal biosensors (Kubik et al., 2005; Vo-Dinh and Cullum, 2000). One

miniaturized biosensor concept makes use of small beams that bend when biological molecules

become captured at the surface inducing a surface stress (see Figure 3).

Figure 3.1 Schematic diagram of a cantilever based biosensor. The yellow molecules bind

specifically to the red molecules on the right hand cantilever and are detected by the bending of

the cantilever (Wang and Branton, 2001).

There are numerous nanoparticles that can be used as biosensors components (Medina et al.,

2007). These work as probes recognizing an analyte or differentiating between analytes of

interest. In such applications some biological molecular species are attached to the surface of the

nanoparticles to recognize, through a key -and-lock mechanism, the target of interest. The probes

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then signal the presence of the target by a change in color, mass or other physical change.

Nanoparticles that are used as elements for biosensors include quantum dots, metallic nanobeads,

silica nanoparticles, magnetic beads, and fullerenes, which are hollow cages of carbon, shaped

like soccer balls.

Other biosensors use nanostructured particles as nano-sieves through which charged molecules

are transported in an electric field. In this case particles with engineered nanopores are used

(Wang and Branton, 2001).

4.5 Nanotubes

Carbon nanotubes discovered in 1991 (Iijima, 1991) are tubular structures like a sheet of graphite

rolled into a cylinder capped at one or both ends by a buckyball. Nanotubes can be single walled

carbon nanotube (SWCNT) or multiwalled carbon nanotube (MWCNT) in concentric fashion.

Single walled nanotube has an internal diameter of 1-2 nm and multiwalled nanotube has a

diameter of 2-25 nm with 0.36 nm distance between layers of MWCNT. These vary in their

length ranging from 1 μm to a few micrometers (Reilly, 2007). These are characterized by

greater strength and stability hence can be used as stable drug carriers. Cell specificity can be

achieved by conjugating antibodies to carbon nanotubes with fluorescent or radiolabelling

(McDevitt et al., 2007). Entry of nanotubes into the cell may be mediated by endocytosis or by

insertion through the cell membrane. Carbon nanotubes can be made more soluble by

incorporation of carboxylic or ammonium groups to their structure and can be used for the

transport of peptides, nucleic acids and other drug molecules. Indium-111 radionuclide labelled

carbon nanotubes are being investigated for killing cancer cells selectively (Reilly, 2007).

Amphotericin B nanotubes has shown increased drug delivery to the interior of cells compared to

amphotericin B administration without nanotubes (Prato et al., 2008). The efficacy of

amphotericin B nanotubes was greater as an antifungal agent compared to amphotericin B alone

and it was effective on strains of fungi which are usually resistant to amphotericin B alone.

Further, there was reduced toxicity to mammalian cells with amphotericin B nanotubes (Prato et

al., 2008).The ability of nanotubes to transport DNA across cell membrane is used in studies

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involving gene therapy. DNA can be attached to the tips of nanotubes or can be incorporated

within the tubes (Prato et al., 2008).showed greater expression of the β galactosidase marker

gene through nanotubes compared to transfer of naked DNA. This confers the advantage of non

immunogenicity in contrast to viral vectors used for gene transfer. Gene silencing studies with

small interfering RNA (siRNA) have been done as a modality of cancer therapy where tumour

cells will be selectively modulated. Functionalized single walled carbon nanotubes can be used

with siRNA to silence targeted gene expression (Zhang et al., 2006).

It was observed that carbon nanotubes, except acetylated ones, when bonded with a peptide

produce a higher immunological response compared to free peptides. This property can be used

in vaccine production to enhance the efficacy of vaccines. Further, it was also found that

compounds bound to nanotubes increase the efficacy of diagnostic methods like ELISA. These

can also be used for designing of biosensors owing to property of functionalization and high

length to diameter aspect ratio which provides a high surface to volume ratio (Pantarotto et al.,

2003; Balasubramanian and Burghard, 2006).

Water insoluble forms of nanotubes like pristine carbon nanotubes have high in vitro toxicity

compared to modified water dispersible forms of nanotubes. It was also seen that the toxic

potential decreases withfunctionalization. Further, functionalization also affects the elimination

of the nanotube. SWCNTs without conjugation to monoclonal antibody have a high renal uptake

and modest liver uptake as compared to SWCNTs with conjugation to monoclonal antibody

having higher liver uptake and lower renal uptake (Reilly, 2007).

Carbon nanotubes and nanowires are also employed for sensing (Kong et al., 2000; Collins et al.,

2000; Cui et al., 2001). The latter can be fabricated out of a semiconductor material and their

size tuned to have a specific conducting property. This, together with the ability to bind specific

analytes on their surface, yields a direct, label-free electrical readout (Cui et al 2001; Patolsky et

al., 2006). These nanowires biosensors allow detecting a wide range of chemical and biological

species, including low concentration of protein and viruses and their application spans from the

medical to the environmental sector. Figure 4 illustrates a silicon nanowires biosensor based on

biorecognition.

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Figure 3.2 Biorecognition on a silicon nanowire biosensor. The surface of the nanowire is

modified with avidin molecules (purple stars) which can selectively bind a streptavidin-

functionalised molecule or nanoparticle (Reilly, 2007).

4.6 Quantum dots

Quantum dots are nanocrystals measuring around 2-10 nm which can be made to fluorescence

when stimulated by light. Their structure consists of an inorganic core, the size of which

determines the colour emitted an inorganic shell and an aqueous organic coating to which

biomolecules are conjugated. The biomolecule conjugation of the quantum dots can be

modulated to target various biomarkers (Iga et al., 2007).

Quantum dots can be used for biomedical purposes as a diagnostic as well as therapeutic tool.

These can be tagged with biomolecules and used as highly sensitive probes. A study done on

prostate cancer developed in nude mice has shown accumulation of quantum dots probe by

enhanced permeability and retention as well as by antibody directed targeting (Gao et al.,

2004).The quantum dots conjugated with polyethylene glycol (PEG) and antibody to prostate

specific membrane antigen (PSMA) were accumulated and retained in the grafted tumour tissue

in the mouse (Gao et al., 2004).

Quantum dots can also be used for imaging of sentinel node in cancer patients for tumour staging

and planning of therapy. This method can be adopted for various malignancies like melanoma,

breast, lung and gastrointestinal tumours (Iga et al., 2007). Quantum dot probes provide real time

imaging of the sentinel node with Near Infra Red (NIR) fluorescence system. The NIR region of

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the electromagnetic spectrum produces reduced background noise and deeper penetration of rays,

of up to 2 to 5 cm into the biological sample. However, the traditional fluorescence dyes yield

low signal intensity when used in NIR region. This limitation is overcome, by using NIR

fluorescence system with quantum dot probes. The fluorescence produced by quantum dots is

much brighter than those produced by conventional dyes when used with NIR fluorescence

system (Amiot et al., 2008).However, the application of quantum dots in a clinical setting has

limitations owing to its elimination factors. Functionalization of the quantum dots which protects

from the toxic core, leads to increase in size of the nanoparticle greater than the pore size of

endothelium and renal capillaries, thus reducing its elimination and resulting in toxicity. Also, in

vivo studies are lacking on the metabolism and excretion of quantum dots (Iga et al., 2007).

4.7 Nanoshells

Nanoshells were developed by West and Halas (West and Halas, 2000). At Rice University as a

new modality of targeted therapy. Nanoshells consist of nanoparticles with a core of silica and a

coating of thin metallic shell. These can be targeted to desired tissue by using immunological

methods. This technology is being evaluated for cancer therapy. (Hirsh et al., 2003) used

nanoshells which are tuned to absorb infra red rays when exposed from a source outside the body

to demonstrate the thermo ablative property of nanoshells. The nanoshells when exposed to NIR

region of the electromagnetic spectrum get heated and cause destruction of the tissue. This has

been studied in both in vitro and in vivo experiments with HER 2 expressing SK-BR-3 human

breast carcinoma cells. The control cells did not lose their viability even after treatment with

nanoshells with non specific anti IgG or PEG and NIR ablation (Lowery et al., 2006).

Nanoshells can also be embedded in a hydrogel polymer containing the drug. After directing the

nanoshells to the tumour tissue by immunological methods, with an infrared laser, these can be

made to get heated up, melting the polymer and releasing the drug at the tumour tissue. Targeting

the drug release avoids the toxicity of cancer chemotherapy drugs. Nanoshells are currently

being investigated for micro metastasis of tumours and also for treatment of diabetes (Freitas,

2005; Kherlopian., 2008).

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Nanoshells are also useful for diagnostic purposes in whole blood immunoassays. Gold

nanoshells can be coupled to antibodies and the size can be modulated so that it responds to NIR

wavelength, which has the ability to penetrate whole blood specimens. With this method it is

possible to detect immunoglobulins at a concentration range of nanograms per millilitre in

plasma and whole blood (Freitas, 2005).

4.8 Nanobubbles

Cancer therapeutic drugs can be incorporated into nanoscaled bubble like structures called as

nanobubbles. These nanobubbles remain stable at room temperature and when heated to

physiological temperature within the body coalesce to form microbubbles. These have the

advantages of targeting the tumour tissue and delivering the drug selectively under the influence

of ultrasound exposure. This results in increased intracellular uptake of the drug by the tumour

cells. It also provides an additional advantage of enabling visualisation of the tumour by means

of ultrasound methods (Klibanov, 2006; Gao et al., 2008). (Rapaport et al., 2007) have

demonstrated the utility of nanobubbles in delivery of drugs like doxorubicin based on in vitro

and in vivo experiments using breast cancer cells MDA MB231 and mice with breast cancer

xenograft respectively. On administration of nanobubble loaded doxorubicin, these reach the

tumour tissue through leaky vasculature and get accumulated at the site of tumour. This is

followed by formation of microbubbles by coalescing of nanobubbles which can be visualized by

ultrasound techniques. When the site is focused with high intensity focused ultrasound (HIFU), it

causes disruption of the microbubbles resulting in release of the drug. The microbubbles retained

the drug in a stable state until stimulated by HIFU. This results in attainment of higher levels of

drug in the target cells and hence reduced toxicity and increased efficacy. This method needs

further exploration for its utility in treatment of various malignancies. Liposomal nanobubbles

and microbubbles are also being investigated for their role as effective non viral vectors for gene

therapy. Nanobubbles combined with ultrasound exposure has shown improved transfer of gene

in both in vitro and in vivo studies (Negishi et al., 2008; Suzuki et al., 2008). Nanobubbles are

also being tried as a therapeutic measure for removal of clot in vascular system in combination

with ultrasound, a process called as sonothrombolysis. This method has advantages of being non

invasive and causing less damage to endothelium (Iverson et al., 2008).

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4.9 Paramagnetic nanoparticles

Paramagnetic nanoparticles are being tried for both diagnostic and therapeutic purposes.

Diagnostically, paramagnetic iron oxide nanoparticles are used as contrast agents in magnetic

resonance imaging. These have a greater magnetic susceptibility than conventional contrast

agents. Targeting of these nanoparticles enables identification of specific organs and tissues

(Cuenca et al., 2006).The use of iron oxide in MRI imaging faces limitations like specificity and

internalization by macrophages (Peng et al., 2008). Paramagnetic nanoparticles conjugated with

antibodies to HER-2/neu which are expressed on breast cancer cells have been used with MRI to

detect breast cancer cells in vitro (Artemov et al., 2003).Study done by (Leuschner et al., 2005)

has demonstrated the in vivo detection of breast cancer cells using paramagnetic nanoparticles

conjugated with luteinizing hormone releasing hormone as breast cancer cells express LHRH

receptors. Thus, use of antibodies to direct the nanoparticle to the target site helped to overcome

problems with specificity of action. Internalization of the nanoparticles by macrophages can be

reduced by treatment with drugs like lovastatin which reduce macrophage receptor expression

for the nanoparticle by reducing the recycling of receptors (Peng et al., 2008). Further, injection

of decoys of nanoparticle can be used to eliminate plasma opsonins and reduce uptake of the

nanoparticles. Also, change of surface charge of the nanoparticle to neutral by covalent coupling

to chemicals leads to an increase in circulation time (Peng et al., 2008).

Monocrystalline iron oxide nanoparticles (MIONs) have been studied by (Knauth et al., 2001) in

magnetic resonance imaging of brain. MIONs help in overcoming the disadvantage of surgically

induced contrast enhancement with traditional contrast agents resulting in misinterpretation

during intra-operative MR imaging of brain. Surgically induced contrast enhancement occurs in

brain due to leak of contrast material from the cut end and oozing blood vessels in brain when

MR imaging is done post- operatively.This is avoided when MIONs are used pre-

operatively.These are rapidly taken up by the tumour cells (Moore et al., 1997), producing long

lasting contrast enhancement of tumour and the remaining nanoparticles are removed from the

circulation by reticuloendothelial system (Weissleder et al., 1989).

19

Magnetic microparticle probes with nanoparticle probes have been used for identification of

proteins like prostate specific antigen. Here magnetic microparticles coated with antibodies

together with nanoprobes with similar coating and a unique hybridized DNA barcode are used.

The microparticle coated with antibody directed against prostate specific antigen combines with

it to form a complex and can be separated by using magnetic separation. The presence of these

separated complexes is determined by dehybridization of the complexed DNA barcode sequence

and polymerase chain reaction for the oligonucleotides. This allows prostate specific antigen

detection at 30 attomolar concentration (Nam et al., 2003).

4.10 Nanosomes

Raoul Kopelman’s group at the University of Michigan, USA, has been working on nanosomes

also called as PEBBLEs (Probes Encapsulated by Biologically Localized Embedding) which

integrate various aspects of medical applications such as targeting, diagnosis and therapy. These

nanosomes are being developed for treatment of various tumours, in particular CNS tumours.

Silica coated iron oxide nanoparticles coated with polyethylene glycol (Xu et al., 2003) and

affixed with targeting antibody and contrast elements like gadolinium are used to access specific

areas of brain involved with tumour. Targeting aids in binding the nanoparticle specifically to the

tumour cells and the contrast elements helps in better detection with magnetic resonance

imaging. Subsequent treatment with laser can destroy the cells loaded with these nanoparticles

by the heat generated by iron oxide particles by absorbing the infra red light. Nanosomes can

also be integrated with a photocatalyst which produces reactive oxygen species when stimulated

by light and destroy the target tissue. This method has advantage over conventional drugs in

being much safer without the adverse effects of cancer chemotherapy drugs and also the absence

of development of drug resistance. Nanosomes are being developed to integrate more and more

components in it for flexibility of its applications (Freitas, 2005).

20

4.11 Dendrimers

Dendrimers are nanostructures produced from macromolecules such as polyamidoamine

(PAMAM), polypropyleneimine and polyaryl ether; and are highly branched with an inner core.

The particle size range is between 1 to 100nm although their sizes are mostly less than 10nm.

About 20 years ago, dendrimer studies centred on their synthesis, physical and chemical

properties while exploration of their biological applications was initiated about thirteen years ago

(Sahoo et al, 2007). The uniqueness of dendrimers is based on their series of

branches,multivalency, well defined molecular weight and globular structure with controlled

surface functionality, which enhances their potential as carriers for drug delivery (Sahoo et al,

2007). Their globular structures and the presence of internal cavities enable drugs to be

encapsulated within the macromolecule interior. Dendrimers have been reported to provide

controlled release from the inner core (Matija, 2004).

Controlled multivalency of dendrimers enables attachment of several drug molecules, targeting

groups and solubilising groups onto the surfaces of the dendrimers in a well defined manner

(Sahoo et al., 2007) Dendrimers are employed due to their size (less than 10nm), ease of

preparation, functionality and their ability to display multiple copies of surface groups for

biological recognition process (Freitas , 2005). Water soluble dendrimers can bind and solubilise

small molecules and can be used as coating agents to protect drugs and deliver to specific sites.

Other applications of dendrimers include catalysis, gene and DNA delivery, biomimetics and as

solution phase supports for combinatorial chemistry (Kostoff et al., 2007).Some of the drug

delivery applications include therapeutic and diagnostic utilization for cancer treatment

(Majumder et al., 2007) enhancement of drug solubility and permeability (dendrimer-drug

conjugates)(Feynman,1960);and intracellular delivery (Smith, 2006).

Dendrimers are also used as contrast agents for imaging.The 1, 4-diaminobutane (DAB) core

dendrimer and the polyamidoamine (PAMAM) dendrimer are well studied commercially

available dendrimers for imaging studies. Renal excretion is the main route of clearance and is

dependent on the size of the particle and more than 60 per cent of injected DAB or PAMAM

dendrimer is cleared from circulation within 15 min (Longmire et al., 2008). Smaller sized

21

dendrimers undergo rapid renal clearance whereas dendrimers with charged surface or

hydrophobic surfaces are rapidly cleared by the liver. Those dendrimers with a hydrophilic

surface escape renal clearance and have a greater circulation time (Duncan and Izzo, 2005).

Cationic dendrimers have a greater potential to cause cytotoxicity compared to anionic

dendrimer or PAMAM dendrimers. It is proposed to cause cell membrane instability and cell

lysis. The toxicity of dendrimer is dependent on the size of the particle and increase with size. It

can be reduced by means of surface modification of the dendrimers with incorporation of PEG or

fatty acids (Svenson and Tomalia, 2005).

4.12 Polymeric nanoparticles

Figure 4. Illustration of Nanospheres,Nanocapsules,Liposomes,Micelles (Svenson and Tomalia ,

2005).

Polymeric nanoparticles are colloidal solid particles with a size range of 10 to 1000nm (Stylios et

al., 2005) and they can be spherical, branched or shell structures. The first fabrication of

nanoparticles was about 35 years ago as carriers for vaccines and cancer chemotherapeutics.

They are developed from non-biodegradable and biodegradable polymers. Their small sizes

enable them to penetrate capillaries and to be taken up by cells, thereby increasing the

accumulation of drugs at target sites. Drugs are incorporated into nanoparticles by dissolution,

entrapment, adsorption, attachment or by encapsulation, and the nanoparticles provide sustained

release of the drugs for longer periods, e.g., days and weeks (Roco, 2003). Nanoparticles

22

enhance immunization by prevention of degradation of the vaccine and increased uptake by

immune cells (Singh et al., 2006). One of the determinants of the extent of uptake by immune

cells is the type of polymer employed. In a study (Miyazaki and Islam, 2007) comparing poly-(_-

caprolactone) (PCL), poly (lactide-coglycolide) (PLGA) and their blend, PCL nanoparticles were

the most efficiently taken up by immune cells due to their hydrophobicity. However, all

polymeric nanoparticles elicited vaccine (diphtheria toxoid) specific serum IgG antibody

response significantly higher than free diphtheria toxoid.

To target drugs to site of action, the drug can be conjugated to a tissue or cell specific ligand or

coupled to macromolecules that reach the target organs. To target an anticancer agent to the

liver, polymeric conjugate nanoparticles which comprised biotin and diamine-terminated poly

(ethylene glycol) with a galactose moiety from lactobionic acid were prepared (Williams, 2008).

Some other applications of nanoparticles include possible recognition of vascular endothelial

dysfunction (Zong et al., 2005);oral deliveryof insulin (Gao et al., 2003); brain drug targeting for

neurodegenerative disorders such as Alzheimer’s disease (Luo et al., 2005); topical

administration to enhance penetration and distribution in and across the skin barrier(Tian et al.,

2007); and pH-sensitive nanoparticles to improve oral bioavailability of drugs such as

cyclosporine A (Shafirovich et al., 2006).

4.13 Solid lipid nanocarriers

Solid lipid nanoparticles (SLN) are nanostructures made from solid lipids such as glyceryl

behenate (Compritol), stearic triglyceride (tristearin), cetyl palmitate and glycerol tripalmitate

(tripalmitin) with a size range of 50 and 1000 nm (Visakhapatnam, 2008). Research interest in

SLN emerged about ten years ago due to their scalability potential. The lipids employed are well

tolerated by the body; large scale production will be cost effective and simple by using high

pressure homogenization. Some of the features of SLN include good tolerability, site-specific

targeting, stability (stabilized by surfactants or polymers), controlled drug release and protection

23

of liable drugs from degradation. However, SLN are known for insufficient drug loading, drug

expulsion after polymorphic transition on storage and relative high water content of the

dispersions. SLN has been studied and developed for parenteral, dermal, ocular, oral, pulmonary

and rectal routes of administration (Zsigmondy, 1926; Roco, 2000-2003; Horton and Khan,

2006;Guo , 2005; Liu et al., 2003).

To overcome the limitations of SLN, nanostructured lipid carriers (NLC) were introduced. NLC

is composed of solid lipids and a certain amount of liquid lipids with improved drug loading and

increased stability on storage thereby reducing drug expulsion (Roco, 2000-2003). NLCs have

been explored for dermal delivery in cosmetics and dermatological preparations (Roco, 2000-

2003).

Lipid drug conjugate (LDC) nanoparticles were introduced to overcome the limitation of types

of drugs incorporated in the solid lipid matrix. Lipophilic drugs are usually incorporated in SLN

but due to partitioning effects during production, only highly potent hydrophilic drugs effective

in low concentrations are incorporated in SLN (Wissing et al., 2004). LDC enables the

incorporation of both hydrophilic (e.g., doxorubicin and tobramycin) and lipophilic (e.g.,

progesterone and cyclosporine A) drugs (Wissing et al., 2004).

4.14 Polymeric micelles

Micelles are formed when amphiphilic surfactant or polymeric molecules spontaneously

associate in aqueous medium to form core-shell structures or vesicles. Polymeric micelles are

formed from amphiphilic block copolymers, such as poly(ethylene oxide)-poly(_-benzyl-

Laspartate) and poly(N-isopropylacrylamide)- polystyrene, and are more stable than surfactant

micelles in physiological solutions (Liu et al., 2003). They were first proposed as drug carriers

about 24 years ago (Liu et al., 2003). The inner core of a micelle is hydrophobic which is

surrounded by a shell of hydrophilic polymers such as poly (ethylene glycol) (Mansoori ,

2002).Their hydrophobic core enables incorporation of poorly water soluble and amphiphilic

drugs while their hydrophilic shell and size (<100nm) prolong their circulation time in the blood

and increase accumulation in tumoural tissues (Liu et al., 2003).

24

Polymeric micelles are able to reach parts of the body that are poorly accessible to liposomes;

accumulate more than free drugs in tumoural tissues due to increased vascular permeability (Liu

et al., 2003). Thus, polymeric micelles can be employed to administer chemotherapeutics in a

controlled and targeted manner with high concentration in the tumoural cells and reduced side

effects. However, the targeting ability of polymeric micelles is limited due to low drug loading

(Balzani, 2005; Teo and Sun, 2006). and low drug incorporation stability (Balzani, 2005). which

cause the loaded drug to be released before getting to the site of action. Consequently,

manipulation of the production parameters and the design of the inner core can improve drug

loading and drug incorporation stability,respectively (Balzani , 2005; Teo and Sun, 2006). Lipid

moieties, such as cholesterol and fatty acyl carnitines, can also be employed to impart good

stability to the polymeric micelles. This is based on increased hydrophobic interaction between

the polymeric chains in the inner core due to presence of fatty acid acyls (e.g.diacyllipid) (Liu et

al., 2003).

Polymeric micelles have been employed for targeted and intracellular delivery (Teo and Sun,

2006) sustained release and parenteral delivery (Liu et al., 2003).

4.15 Nanocapsules

Nanocapsules are spherical hollow structures in which the drug is confined in the cavity and is

surrounded by a polymer membrane (Romig et al., 2007).They were developed over 30 years

ago. Sizes between 50 and 300nm are preferred for drug delivery and they may be filled with oil

which can dissolve lipophilic drugs. They have low density, high loading capacity and are taken

up by the mononuclear phagocyte system, and accumulate at target organs such as liver and

spleen (Shea, 2005).

Nanocapsules can be employed as confined reaction vessels, protective shell for cells or

enzymes, transfection vectors in gene therapy, dye dispersants, carriers in heterogenous catalysis,

imaging and drug carriers (Tratnyek and Johnson , 2006; Roco, 2001). They are known to

25

improve the oral bioavailability of protein and peptides which include insulin, elcatonin and

salmon calcitonin (Romig et al., 2007; Salamanca-Buentello et al., 2005). Encapsulation of drugs

such as ibuprofen(Shea , 2005). within nanocapsules protects liable drugs from degradation,

reduces systemic toxicity, provide controlled release and mask unpleasant taste (Singh, 2007).

Due to their high stability and low permeability, drugs may not be loaded into the capsules after

formulation and also the release of the drug at target site may be difficult. To improve on their

permeability, they are made responsive to physiological factors such as pH (Tegart, 2008).

4.16 Nanoemulsions

Nanoemulsions are emulsions with droplet size below 1μ but usually between 20 and 200nm

(Malsch, 1999; Renn and Roco, 2006). Unlike microemulsions which are white in colour due to

their light scattering ability, nanoemulsions whose nanosize is often smaller than visible

wavelength, are transparent (Malsch, 1999; Dunphy et al., 2000-2004). Nanoemulsions are

biodegradable, biocompatible, easy to produce and used as carriers for lipophilic drugs which are

prone to hydrolysis. They are employed as a sustained release delivery system for depot

formation via subcutaneous injection (Renn and Roco , 2006). They enhance gastrointestinal

absorption and reduce inter- and intra-subject variability for various drugs. Due to their very

large interfacial area, they exhibit excellent drug release profile (Cobb and Macoubrice, 2004).

Nanoemulsions have been studied and developed for parenteral, oral, ocular, pulmonary and

dermal deliveries (Malsch, 1999).

Stability against sedimentation is attained based on the nano size of the droplets because the

sedimentation rate due to gravity is less than Brownian movement and diffusion (Malsch, 1999).

Unlike microemulsions, nanoemulsions are metastable and can be destabilized by Ostwald

ripening whereby the small droplets dissolve and their mass is taken up by the large droplets and

depletion induced flocculation due to addition of thickening polymers. When this happens, the

nanoemulsion becomes opaque and creaming will occur (Roco, 2003). However, addition of a

small amount of a second oil with low solubility into the aqueous phase and addition of a second

surfactant may reduce Ostwald ripening (Malsch, 1999). Also, a number of factors during

production should be controlled (Dunphy et al., 2000-2004). These factors include selecting an

26

appropriate composition, controlling the order of addition of components, applying the shear in a

manner that will effectively rupture the droplets, and ensuring that the dispersed phase molecules

are insoluble in the continuous phase so that Ostwald ripening does not occur rapidly (Dunphy et

al., 2000-2004).

4.17 Ceramic nanoparticles

Ceramic nanoparticles are particles fabricated from inorganic compounds with porous

characteristics such as silica, alumina and titania (Oberdörster et al., 2005; Nimesh et al., 2006;

Soppimath et al., 2001). They can be prepared with the desired size, shape and porosity. Their

sizes are less than 100nm and are able to avoid uptake by the reticulo-endothelial system as

foreign bodies. Entrapped molecules such as drugs, proteins and enzymes are protected from

denaturation at physiological pH and temperature as neither swelling nor change in porosity

occurs (Soppimath et al., 2001).Hence, they are effective in delivering proteins and genes.

However, these particles are not biodegradable and so there is concern that they may accumulate

in the body and cause harmful effects (Nimesh et al., 2006).

4.18 Metallic nanoparticles

Metallic nanoparticles include iron oxide, gold, silver, gadolinium and nickel which have been

studied for targeted cellular delivery(Jung et al., 2000).Gold exhibits favourable optical and

chemical properties at nanoscale for biomedical imaging and therapeutic applications (Nimesh et

al., 2006). It can be manipulated to obtain the desired size in the range of 0.8 to 200nm. The

surface can be modified with different functional groups for gene transfection, modified into

gene delivery vector by conjugation and also modified to target proteins and peptides to the cell

nucleus (Jung et al., 2000; Italia et al., 2007). Gadolinium has been studied for enhanced tumour

targeted delivery by modification of the nanoparticles with folate, thiamine and poly (ethylene

glycol). Modification with folate was reported to enhance the recognition, internalization and

retention of gadolinium nanoparticles in tumour cells (Jung et al., 2000).

27

4.19 Carbon nanomaterials

These include carbon nanotubes and fullerenes. Fullerenes are carbon allotrope made up of 60 or

more carbon atoms with a polygonal structure. Nanotubes have been used for their high electrical

conductivity and excellent strength (Nimesh et al., 2006). These materials are being studied for

therapeutic applications. Fullerenes can be functionalized for delivery of drugs and biomolecules

across cell membrane to the mitochondria (Jung et al., 2000). Carbon nanotubes’ unique

properties including low cytotoxicity and good biocompatibility attract their use as vector system

in target delivery of drugs, proteins and genes (Jung et al., 2000). However,toxicity of carbon

nanotubes is of concern (Sahoo and Labhasetwar, 2003). Carbon nanotubes may cause

inflammatory and fibrotic reactions.

Figure 5: Illustration of some nanostructures A) Spherical polymeric nanoparticle; B) Liposome;

C)Solid lipid nanoparticles – solid lipid enclosed within; D) Nanoemulsion – liquid enclosed

within; E)Nanocapsule – hollow; F) Carbon nanotube; G) Dendrimer; I) Polymeric micelle.

(Ochekpe et al., 2009).

28

5. Nanosurgery

Present-day nanomedicine exploits carefully structured nanoparticles such as dendrimers (Borges

and Schengrund, 2005), carbon fullerenes (buckyballs) (Mashino et al., 2005) and Nanoshells

(O’Neal et al., 2004) to target specific tissues and organs. These nanoparticles may serve as

diagnostic and therapeutic antiviral, antitumor or anticancer agents. But as this technology

matures in the years ahead, complex nanodevices and even nanorobots will be fabricated, first of

biological materials but later using more durable materials such as diamond to achieve the most

powerful results.

5.1 Early vision

The first and most famous scientist to voice this possibility was the late Nobel physicist Richard

P. Feynman. In his remarkably prescient 1959 talk ‘‘There’s Plenty of Room at the Bottom,’’

Feynman proposed employing machine tools to make smaller machine tools, these are to be used

in turn to make still smaller machine tools, and so on all the way down to the atomic level,

noting that this is ‘‘a development which I think cannot be avoided.’’ (Feynman, 1960)

Feynman was clearly aware of the potential medical applications of this new technology. He

offered the first known proposal for a nanorobotic surgical procedure to cure heart disease: ‘‘a

friend of mine (Albert R. Hibbs) suggests a very interesting possibility for relatively small

machines. He says that, although it is a very wild idea, it would be interesting in surgery if you

could swallow the surgeon. You put the mechanical surgeon inside the blood vessel and it goes

into the heart and looks around. (Of course the information has to be fed out.) It finds out which

valve is the faulty one and takes a little knife and slices it out. .[Imagine] that we can

manufacture an object that maneuvers at that level!. Other small machines might be permanently

incorporated in the body to assist some inadequately functioning organ.’’ (Feynman, 1960)

29

5.2 Medical microrobotics

There are ongoing attempts to build microrobots for in vivo medical use. In 2002, at Tohoku

University developed tiny magnetically driven spinning screws intended to swim along veins and

carry drugs to infected tissues or even to burrow into tumors and kill them with heat (Freitas,

2005). In 2003, the ‘‘MR-Sub’’ project of Martel’s group at the NanoRobotics Laboratory of

Ecole Polytechnique in Montreal tested using variable MRI magnetic fields to generate forces on

an untethered microrobot containing ferromagnetic particles, developing sufficient propulsive

power to direct the small device through the human body (Freitas, 2005). Brad Nelson’s team at

the Swiss Federal Institute of Technology in Zurich continued this approach. In 2005, they

reported the fabrication of a microscopic robot small enough (w200 mm) to be injected into the

body through a syringe. They hope that this device or its descendants might someday be used to

deliver drugs or perform minimally invasive eye surgery (Freitas, 2005). Nelson’s simple

microrobot has successfully maneuvered through a watery maze using external energy from

magnetic fields, with different frequencies that are able to vibrate different mechanical parts on

the device to maintain selective control of different functions. Gordon’s group at the University

of Manitoba has also proposed magnetically controlled ‘‘cytobots’’ and ‘‘karyobots’’ for

performing wireless intracellular and intranuclear surgery (Freitas, 2005).

5.3 Manufacturing medical nanorobots

The greatest power of nanomedicine will emerge, perhaps in the 2020s, when we can design and

construct complete artificial nanorobots using rigid diamondoid nanometer-scale parts like

molecular gears (Fig. 8) and bearings (Freitas , 2005).

30

Figure 6. A molecular planetary gear is a mechanical component that might be found inside a

medical nanorobot. The gear converts shaft power from one angular frequency to another. The

casing is a strained silicon shell with predominantly sulfur termination, with each of the nine

planet gears attached to the planet carrier by a carbon-carbon single bond. The planetary gear

shown here has not been built experimentally but has been modeled computationally.

5.4 Respirocytes and microbivores

The ability to build complex diamondoid medical nanorobots to molecular precision, and then to

build them cheaply enough in sufficiently large numbers to be useful therapeutically, will

revolutionize the practice of medicine and surgery (Freitas, 2005).The first theoretical design

study of a complete medical nanorobot ever published in a peer-reviewed journal (in 1998)

described a hypothetica l artificial mechanical red blood cell or ‘‘respirocyte’’ made of 18 billion

precisely arranged structural atoms (Freitas, 1998). The respirocyte is a bloodborne spherical 1-

mm diamondoid 1000-atmosphere pressure vessel with reversible molecule-selective surface

pumps powered by endogenous serum glucose. This nanorobot would deliver 236 times more

oxygen to body tissues per unit volume than natural red cells and would manage carbonic

acidity, controlled by gas concentration sensors and an onboard nanocomputer. A 5-cc

31

therapeutic dose of 50% respirocyte saline suspension containing 5 trillion nanorobots could

exactly replace the gas carrying capacity of the patient’s entire 5.4 l of blood.

Nanorobotic artificial phagocytes called ‘‘microbivores’’ (Fig. 9)

Figure 7. Nanorobotic artificial phagocytes called ‘‘microbivores’’could patrol the bloodstream,

seeking out and digesting unwanted pathogens (Freitas, 2005).

Could patrol the bloodstream, seeking out and digesting unwanted pathogens including bacteria,

viruses, or fungi (Freitas, 2005).

6. Nanotechnology in drug delivery

Generally, nanostructures have the ability to protect drugs encapsulated within them from

hydrolytic and enzymatic degradation in the gastrointestinal tract; target the delivery of a wide

range of drugs to various areas of the body for sustained release and thus are able to deliver

drugs, proteins and genes through the peroral route of administration (Nimesh et al., 2006;

Soppimath et al., 2001; Jung et al., 2000). They deliver drugs that are highly water insoluble; can

bypass the liver, thereby preventing the first pass metabolism of the incorporated drug (Italia et

al., 2007; Sahoo and Labhasetwar , 2003). They increase oral bioavailability of drugs due to

their specialized uptake mechanisms such as absorptive endocytosis and are able to remain in the

32

blood circulation for a longer time, releasing the incorporated drug in a sustained and continuous

manner leading to less plasma fluctuations thereby minimizing side-effects caused by drugs

(Italia et al., 2007). Due to the size of nanostructures, they are able to penetrate into tissues and

are taken up by cells, allowing efficient delivery of drugs to sites of action. The uptake of

nanostructures was found to be 15-250 times greater than that of microparticles in the 1-10μm

range (Panyam and Labhasetwar , 2003).

Through the manipulation of the characteristics of polymers, release of drug from nanostructures

can be controlled to achieve the desired therapeutic concentration for the desired duration. For

targeted delivery, nanostructures can be conjugated with targeting moieties such that the linkage

between the polymer and the active substance can be manipulated to control the site and duration

at which the drug is released. The linkage may be achieved by incorporation of amino acids,

lipids, peptides or small chains as spacer molecules (Peppas, 2004). Drug targeting is crucial in

chemotherapy, where a drug delivery system can target only the malignant tumour while

shielding the healthy cells from uniform distribution of chemotherapeutics in the body and their

harmful effects.

The use of nanostructures such as polymeric nanoparticles is a non-invasive approach of

penetrating the blood brain barrier for management of neurodegenerative disorders,

cerebrovascular and inflammatory diseases (Garcia-Garcia et al., 2005; Ringe et al., 2004).

Research and development of new drugs are capital- and time- intensive which requires that

pharmaceutical companies, in addition,search for other means of meeting up with market

demands. New drug delivery methods enable pharmaceutical companies reformulate existing

drugs in the market. Nanotechnology is strategic in developing drug delivery systems which can

expand drug markets. Nanotechnology can be applied to reformulate existing drugs thereby

extending products’ lives, enhance their performance, improve their acceptability by increasing

effectiveness, as well as increase safety and patient adherence, and ultimately reduce health care

costs (Sahoo and Labhasetwar, 2003; Hughes, 2005). Nanotechnology may also enhance the

performance of drugs that are unable to pass clinical trial phases (Hughes, 2005). It provides

33

drug delivery carriers, as well as treatment and management of chronic diseases which include

cancer, HIV/AIDS and diabetes.

Table 2

Examples of drug delivery technologies in relation to the current nanotechnology revolution

(Hughes , 2005).

Period Before Nanotechnology

(Past)

Transition Period

(Present)

Mature

Nanotechnology

(Future)

Technology Emulsion-based

preparation of nano/micro

particles

Nano/micro fabrication Nano/micro

manufacturing

Examples • - Liposomes

• -Polymer micelles

• - Dendrimers

• - Nanoparticles

• - Nanocrystals

• - Microparticles

• -Microchip

systems

• -Microneedle

transdermal

delivery systems

• - Layer-by-layer

assembled systems

• - Microdispensed

particles

• -Nano/micro

machines for

scale-up

production

7. Commercially available nano drug delivery systems

Despite the challenges which include the huge volume of expenditure involved and the

regulatory stages (preclinical and clinical stages – Phases 1 - 4) which are mandatory in order to

obtain regulatory approval before a drug can get into the market, some nano drug delivery

systems have made it to the market. Table 3 shows the list of some of nano drug delivery

systems in the market:

34

Table 3: Nano drug delivery systems in the market(Wagner et al., 2006)

35

8. Conclusion

The nanotechnology will help to improve health by enhancing the efficacy and safety of

nanosystems and nanodevices. Moreover, early diagnosis, implants with improved properties,

cancer treatment and minimum invasive treatments for heart disease, diabetes and other diseases

are anticipated. In the coming years, nanotechnology will play a key role in the medicine of

tomorrow providing revolutionary opportunities for early disease detection, diagnostic and

therapeutic procedures to improving health and enhancing human physical abilities, and enabling

precise and effective therapy tailored to the patient. Nanomedicine is in infancy, having the

potential to change medical research dramatically in the 21st century. Nanomedical devices can

be applied for analytical, imaging, detection, diagnostic and therapeutic purposes and

procedures, such as targeting cancer, drug delivery, improving cell-material interactions,

scaffolds for tissue engineering, and gene delivery systems, and provide innovative opportunities

in the fight against incurable diseases. Many novel nanoparticles and nanodevices are expected

to be used, with an enormous positive impact on human health. Over the next ten to twenty years

nanotechnology may fundamentally transform science, technology, and society offering a

significant opportunity to enhance human health in novel ways, especially by enabling early

disease detection and diagnosis, as well as precise and effective therapy tailored to the patient.

36

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