applications and synthesis of nanoparticles in medicine

www.wjpr.net Vol 5, Issue 7, 2016.

365

Sarkar World Journal of Pharmaceutical Research

APPLICATIONS AND SYNTHESIS OF NANOPARTICLES IN

MEDICINE

Dr. Leena H. Sarkar

Department of Chemistry, J.V.M’s Degree College, Airoli, Navi Mumbai 400 708, India.

ABSTRACT

Nanoparticles are materials with dimensions of the nanoscale i.e.,

under 100 nm in size. Recently researchers have developed interest in

synthesis and applications of nanotechnology. It is considered as most

active area of research and advancements have been made in the field

of medicine, clinical applications, magnetic resonance imaging and

drug delivery systems. However, in some cases nanoparticles also

bring with them unique challenges to our society and environment, due

to their toxic nature. This review aims to highlight the major

contributions of nanoparticles to modern medicine and also discuss the

effects of nanoparticles on environment and society.

KEYWORDS: nanoparticles, contrast agents, drug delivery, tumors, quantum dots, cancer,

toxicity.

INTRODUCTION

Nanoparticles are particles between 1 and 100 nanometers in size.[1]

They are also referred as

“zero-dimensional” nanomaterials. In nanotechnology, a particle is defined as a small object

that behaves as a whole unit with respect to its transport and properties. Particles are further

classified according to diameter.[2]

Nanoparticles show unique properties compared to the

bulk metals therefore a lot of research work has been reported for the synthesis and

applications of metal nanoparticles.[3]

Nanoparticles have a number of novel optical, electronic, magnetic, structural properties,

chemical reactivity, energy absorption, and biological mobility compared with the same

materials at bulk volume by virtue of their size, making them attractive.

There are two main approaches for the synthesis of nanoparticles: top-down and bottom-up.

In top-down approach the material size is reduced from large to nanoscale, whereas in the

World Journal of Pharmaceutical Research SJIF Impact Factor 6.805

Volume 5, Issue 7, 365-379. Review Article ISSN 2277– 7105

*Corresponding Author

Dr. Leena H. Sarkar

Department of Chemistry,

J.V.M’s Degree College,

Airoli, Navi Mumbai 400

708, India.

Article Received on

24 April 2016,

Revised on 15 May 2016,

Accepted on 03 June 2016

DOI: 10.20959/wjpr20167-6467


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bottom-up approach nanomaterials are synthesised by starting from the atomic level.[4,5]

The

top-down approach often uses the traditional methods where externally controlled tools are

used to cut, mill, and shape materials into the desired shape and order. Bottom-up approach

uses the chemical properties of single molecules to (a) self-organize or self-assemble into

some useful conformation, or (b) rely on positional assembly. The biggest problem with top

down approach is that it introduces internal stress, contaminations, surface defects leading to

imperfection of structure and crystallographic damage. These imperfections lead to extra

challenges in the fabrication. But this approach leads to the bulk production of nano

materials. Regardless of the defects produced by top down approach, they continue to play an

important role in the synthesis of nano structures. Though the bottom up approach is an old

concept observed in nature and has been used in industries for a long time. For example,

production of salt in chemical industry. Bottom up approach gives nano structures with less

defects and more homogeneous chemical composition.

These materials can be synthesized by several methods which include solid-phase, liquid-

phase and gas-phase processes. The solid-phase techniques include mechanical ball

milling[6,7]

and mechano chemical[7]

, the liquid-phase techniques which include laser

ablation[8,9]

, exploding wire[10]

, solution reduction[11]

, and decomposition process[12,13]

,

whereas the gas-phase processes include gas evaporation[14,15]

, exploding wire[16,17]

, and laser

ablation process.[18]

There are large number of applications of nanoparticles in medicine. This article reviews

synthesis, the role of nanoparticles in medicine, medical imaging and drug/gene delivery.

Also the effect of nanoparticles on environment has been discussed.

ROLE OF NANOPARTICLES (NPs) IN MAGNETIC RESONANCE IMAGING

(MRI)

Cancer is a disease for which mortality rate is very high. Treatment methods include surgery,

chemotherapy and radiation therapy. However, the results of the treatment are not positive in

many cases. The reasons behind this being ineffective early diagnosis, insufficient drug

concentrations reaching the tumour cells, adverse effects of drugs. Thus, the important issues

in improving treatment regimens are (i) development of advanced imaging technologies for

early diagnosis and (ii) utilization of targeting moieties to specifically and efficiently deliver

drugs to tumour tissues.


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Harisinghani et al[19]

used SPIO nanoparticles to detect small metastases in the lymph node in

human patients with prostate cancer which would not be detected by conventional MRI.

SPIO nanoparticles allow the visualization of metastases that cannot be clearly observed by

conventional MRI. The significance of this work is that patients with localized disease have

the option of early treatment by surgery without being restricted to radiation therapy, the

primary treatment for advanced-stage patients.

Huh et al[20]

described the use of SPIO nanoparticles to detect cancer in vivo using a mouse

xenograft model. SPIO nanoparticles were prepared by the thermal decomposition of iron

acetylacetonate and made water-soluble by binding with 2, 3-dimercaptosuccinic acid and

then conjugated to herceptin, a cancer-targeting antibody. When administered intravenously

to mice, a rapid change was observed in the T2-weighted MRI signal from the tumor located

in the thigh of the animals.

Recently researchers at Imperial College London[21]

, have designed a new self-assembling

nanoparticle that boosts the effectiveness and sensitivity of Magnetic Resonance Imaging

(MRI) scanning, targets tumours and helps doctors for earlier diagnosis of cancer.

The nanoparticle is coated with a special protein, which looks for specific signals given off

by tumours, and when it finds a tumour it begins to interact with the cancerous cells. This

interaction strips off the protein coating, causing the nanoparticle to self-assemble into a

much larger particle so that a more powerful signal is obtained and a clearer MRI image of

the tumour is visible. This would enable doctors for faster detection of cancer and patients to

receive effective treatment sooner.

ROLE OF NANOPARTICLES IN OPTICAL IMAGING

Conventional imaging of cells and tissue sections is performed by loading organic dyes into

the sample. Dyes such as fluorescein isocyanate (FITC) and rhodamine are often attached to

biomolecules that selectively bind to cells or cell components through ligand/receptor

interactions. Inadequate fluorescence intensity and photobleaching i.e. gradual decrease in

fluorescence intensity are observed in this mode.

Fluorescent nanoparticles (NPs), such as organic dye-doped NPs, quantum dots enable highly

sensitive optical imaging of cancer at cellular and animal level.


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NPs, when conjugated with several functional molecules like targeting moieties and imaging

probes, provides new potentials for clinical therapies and diagnostics. NP-based drug-

delivery systems based on polyethyleneimine (PEI), liposomes, micelles and silica NPs help

in easy drug delivery and reduce drug side effects.[22]

The core of the nanoparticle employs a phenomenon called plasmonics. In plasmonics,

nanostructured metals such as gold and silver[23]

resonate in light and concentrate the

electromagnetic field near the surface. In this way, fluorescent dyes are enhanced, appearing

about tenfold brighter than their natural state when no metal is present. When the core is

etched, the enhancement goes away and the particle becomes dim.

Quantum dots (QDs) are made of inorganic semiconductor molecules. They emit strong

fluorescent light under ultraviolet (UV) illumination. The wavelength of the emitted

fluorescent light depends on particle size. When QDs are excited by giving energy of a

specific wavelength, in the form of a photon an electron jumps from the valence band to the

conduction band and leaves behind a “hole”. When the excitation ceases, electrons come

back to the valence band, by emitting energy in form of light. Larger QDs have more

electron-hole pairs and are therefore capable of absorbing and releasing more energy. The

wavelength of emitted light decreases as QD size increases as energy is inversely

proportional to wavelength. Hence QDs emit light that is far more intense as compared to

conventional organic dyes. This is a major advantage in 3-D tissue imaging where

photobleaching is a major concern.[24]

QDs made of CdTe and capped with CdSe are capable of light emission under near infrared

excitation. This helps to locate lymph nodes up to 1 cm below the skin without the need for

surgical incisions.[25]

Akerman et al showed that QDs can be targeted to specific organs within the body by coating

them with appropriate molecules.[26]

TARGETING OF TUMORS USING NANOPARTICLES

Most anti-cancer drugs cannot differentiate between cancerous and normal cells, leading to

systemic toxicity and adverse effects. The maximal allowable dose is limited due to severe

side effects of the drugs to be delivered in a living system, resulting in inadequate drug


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concentrations reaching the tumour cells. NPs can deliver anti-cancer drugs to tumour sites

efficiently benefiting cancer patients.[27]

Gold nanoparticles are emerging as promising agents for cancer therapy and are being

investigated as drug carriers, photothermal agents. Tumour targeting can be achieved by

actively binding tumour-specific recognition molecules such as epidermal growth factor

(EGF), transferrin, folic acid or monoclonal antibodies to nanoparticles.[28,29,30]

Scientists at UC Santa Barbara[23]

have designed silver nanoparticles that are spherical in

shape and are encased in a shell coated with a peptide that enables it to target tumor cells.

The shell is etchable so those nanoparticles that don’t hit their target can be broken down and

eliminated.

UCSB’s Ruoslahti Research Laboratory has also developed a simple etching technique which

uses biocompatible chemicals to rapidly disassemble and remove the silver nanoparticles

outside living cells. This method leaves only the intact nanoparticles for imaging or

quantification, thus revealing which cells have been targeted and how much each cell

internalized. “The disassembly is an interesting concept for creating drugs that respond to a

certain stimulus. It also minimizes the off-target toxicity by breaking down the excess

nanoparticles so they can then be cleared through the kidneys.” Since the nanoparticle has a

core shell structure, by varying its exterior coating the efficiency of tumor targeting and

internalization can be compared. Switching out the surface agent enables the targeting of

different diseases.

NANOPARTICLES IN DRUG AND GENE DELIVERY

Nowadays in drug therapy, a drug is transported to the place of action by using controlled

drug delivery systems (DDS)[31]

as a result, its effectiveness can be increased and its

influence on vital tissues and undesirable side effects can be reduced. Also, more drug

accumulates at the target site and so lower doses of drugs are required.

A drug may be adsorbed or covalently attached to the nanocarriers surface or else it can be

encapsulated into it. Covalent linking has the advantage over other ways of attaching as it

enables to control the number of drug molecules connected to the nanocarrier, i.e., a precise

control of the amount of the drug will be delivered. Cell-specific targeting with nanocarriers


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may be accomplished by using active or passive mechanisms. Nanocarriers used for medical

applications have to be biocompatible and nontoxic.

SLN (solid lipid nanoparticles), NLC (nanostructured lipid carriers) and LDC (lipid drug

conjugates) are types of carrier systems based on solid lipid matrix i.e., lipids solid at the

body temperature.[32]

They have been exploited for the dermal[33]

, peroral[34]

, parenteral[35]

,

ocular[36]

, pulmonary[37]

, and rectal application.

Polymeric nanoparticles (PNPs) are structures obtained from synthetic polymers, such as

poly-e-caprolactone[38]

, polyacrylamide[39]

and poly-acrylate[40]

, or natural polymers, e.g.,

albumin[41]

, gelatin.[42]

Based on in vivo behavior, PNPs may be classified as biodegradable,

i.e., poly(L-lactide) (PLA)[43]

, poly-glycolide (PGA).[44]

Nanocarriers composed of

biodegradable polymers undergo hydrolysis in the body, producing biodegradable metabolite

monomers, such as lactic acid and glycolic acid. Kumari et al.[45]

reported a minimal systemic

toxicity associated with using of PLGA poly(lactic-co-glycolic acid) for drug delivery or

biomaterial applications. These biodegradable polymeric nanocarriers used for drug delivery

are stable in blood, non-toxic, and non-thrombogenic. They are also non-immunogenic as

well as non-proinflammatory, and they neither activate neutrophils nor affect

reticuloendothelial system.[46]

Some nanomers have dendritic structure eg. glycogen, amylopectin, and proteoglycans.[47]

They consist of a core with at least two identical functional groups, dendrons and surface

active groups. Dendrimers cytotoxicity and use of dendrimers in medical applications,

biocompatibility and physicochemical properties of dendrimers are determined by surface

functional groups.[48]

For example, changing the surface amine groups into hydroxyl ones may result in lower

levels of cytotoxicity. The presence of several surface functional groups enables a

simultaneous interaction with a number of receptors increasing its biological activity. The

drug may either be encapsulated in the internal structure of dendrimers[49]

when drugs are

labile, toxic, or poorly Soluble or else it can be chemically attached or physically adsorbed on

dendrimers surface[50]

which helps to control quantity of drugs on dendrimers surface by

controlling the number of covalent bonds.[51]


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The surface of dendrimers provides an excellent platform for an attachment of specific

ligands, which may include folic acid[51]

, antibodies[52]

, cyclic targeting peptides – arginine-

glycine-aspartic acid (RGD).[53]

Poly(amido amide) (PAMAM) is a dendrimer which is

frequently used in biomedical applications.

Carbon nanotubes (CNTs) and nanohorns (CNH) are used as nanocarriers. Biocompatibility

of these nanotubes can be increased by chemical modification of their surface.[54]

Such

modification can be implemented by covalent anchoring of PAMAM dendrimers[55]

,

amphiphilic diblock copolymers[56]

or PEG layers[57]

on CNTs surface. Due to their

mechanical strength, SWCNTs (Single Walled Carbon Nanotubes have been used to improve

properties of other carriers, e.g., polymeric or non-polymeric composites.[58]

Drug

immobilization in carbon nanocarriers can be done by - encapsulation of a drug in the carbon

nanotube[59]

, chemical adsorption on the surface or in the spaces between the nanotubes (by

electrostatic, hydrophobic, p-p interactions and hydrogen bonds)[60,61]

, and attachment of

active agents to functionalized carbon nanotubes (f-CNTs). Encapsulation has the advantage

over the two remaining methods as the drug is protected from degradation during its transport

to the cells and is released only in specific conditions.[62]

To prevent the unwanted release of

the drug, the open ends of CNTs are sealed with polypyrrole (PPy) films.[63]

CANCER

Nanoparticles are used for the treatment of various types of cancers. Paclitaxel is used for

treatment of various types of cancer (such as skin, ovarian, lung and oesophageal.[64,65,66]

This drug interferes with the functions of cancer cells by microtubule stabilization, resulting

in apoptosis.[67]

A major shortcoming of this approach is the side effects associated with

Cremophor®, including hypersensitivity reactions, necessitating the administration of steroids

and antihistamines as premedications [68]. Abraxane® is a different form of paclitaxel where

paclitaxel is embedded within nanoparticles of a natural polymer, albumin, using a high-

pressure emulsification process. This form eliminates the side effects of Cremophor®[69]

and

the albumin carrier improves transport of the drug from the bloodstream to the tumor site and

allows higher drug dosing compared with Taxol.®

If a large number of cancerous cells are removable, then they should be removed surgically,

but even after removing a bigger tumor, residual cancer cells can be left behind in the area.

These residual cells can grow into tumors, leaving the possibility of the cancer recurring.

Detecting single residual cancer cells is not easy, however a cluster as small as three cancer


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cells can be detected using the gold nanoparticle method. This method then becomes a very

useful option for two reasons: 1) detecting residual cancer cells, indicating whether more

tissue needs to be removed and 2) using this method to obliterate residual cancer cells. The

researchers had success with both methods, resulting in no cancer reappearance in their trials.

Removing residual cancer cells with nanoparticles was deemed a new type of surgery by the

researchers. They called it “PNB nanosurgery” which stands for Plasmonic Nano Bubble

nanosurgery.[70]

NEURODEGENERATIVE DISEASES

Treatment for neurodegenerative diseases is a challenge due to difficulty in Drug delivery to

the central nervous system.[71]

Nanoparticles made from poly (hexadecyl cyanoacrylate) and

related compounds have been shown to facilitate drug transport across the blood–brain barrier

(BBB). Kreuter et al[72, 72a]

adsorbed dalargin (an analgesic) onto poly(butyl cyanoacrylate)

(PBCA) nanoparticles and demonstrated penetration across the BBB in rats. More recently,

Siegemund et al[73]

showed how PBCA nanoparticles loaded with thioflavins can target

fibrillar amyloid β in a murine model of Alzheimer’s disease.

HIV/AIDS

De Jaeghere et al[74]

investigated the delivery of an HIV-1 protease inhibitor, CGP 70726,

using pH-sensitive nanoparticles made from a copolymer of methacrylic acid and ethyl

acrylate. This copolymer is commercially available under the name Eudragit®

L100–55. The

HIV-1 Tat protein has recently emerged as a potential candidate for a prophylactic or

therapeutic vaccine against HIV-1/AIDS.[75]

Study is still going on for solutions for the

disease.

Besides this nanoparticles have also been effectively used in the treatment of ocular

diseases[76,77]

and respiratory disease.[78,79,80]

EFFECTS OF NANOPARTICLES ON ENVIRONMENT AND SOCIETY

With the development of nanotechnology, the effects of nanomaterials, on the environment

and public health has received considerable attention in recent years. On one hand,

nanotechnological innovations have helped to improve the health of people and at the same

time different kinds of risks are associated with different nanoparticles.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673971/#b36-ijn-2-129

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673971/#b67-ijn-2-129


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Air pollution affects human health. Nanoparticles can be present in inhaled particulate matter

and may get deposited in the lungs. They can move from the lungs to other organs such as the

brain, the liver and possibly the foetus in pregnant women. The effects of inhaled

nanoparticles in the body may include lung inflammation, heart problems and other health

problems.

Studies have been done and toxic effects of Quantum dots[81,82]

; metallic, polymeric and

liposomal nanoparticles[83,84,85,86]

have been explored.

CONCLUSION

Nanoparticles have been recently used in the field of medicine for medical imaging,

drug/gene delivery. Innovations are also associated with certain harmful effects on

environment and society. We have to overcome these challenges.

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