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NANOPARTICLES AND NANOTECHNOLOGY: AN APPROACH FOR

CANCER THERAPY

*Dr. Priyanka Khokhar

A.P. Meerut Uttar Pradesh India 250001.

ABSTRACT

Nanoparticles (size in nanometer range) provide a new mode of cancer

drug delivery functioning as a carrier for entry through fenestrations in

tumour vasculature allowing direct cell access. These particles allow

exquisite modification for binding to cancer cell membranes, the

microenvironment, or to cytoplasmic or nuclear receptor sites. There

are various nanoparticles that can fight against the cancerous cells but

few are very challenging and promising like gold nanoparticles as

discussed in this article. Gold nanoparticles are emerging as promising

agents for cancer therapy and are being investigated as drug carriers,

photothermal agents, contrast agents and radio-sensitisers. To help this, nanotechnology

provides a great deed. The use of nanotechnology in cancer treatment offers some exciting

possibilities, including the possibility of destroying cancer tumors with minimal damage to

healthy tissue and organs, as well as the detection and elimination of cancer cells before they

form tumors. Most efforts to improve cancer treatment through nanotechnology are at the

research or development stage. However the effort to make these treatments a reality is

highly focused.

KEYWORDS: Definition, types and applications of nanoparticles. Gold nanoparticles as

novel agent for cancer therapy and Nanotechnology in cancer treatment.

INTRODUCTION

Cancer is a group of diseases involving abnormal cell growth with the potential to invade or

spread to other parts of the body.[1][2]

Not all tumors are cancerous; benign tumors do not

spread to other parts of the body.[2]

Possible signs and symptoms include a lump, abnormal

bleeding, prolonged cough, unexplained weight loss and a change in bowel

movements.[3]

While these symptoms may indicate cancer, they may have other

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 6.647

Volume 6, Issue 2, 412-432 Review Article ISSN 2278 – 4357

*Corresponding Author

Dr. Priyanka Khokhar

A.P. Meerut Uttar Pradesh

India 250001.

Article Received on

09 Dec. 2016,

Revised on 29 Dec. 2016, Accepted on 19 Jan. 2017

DOI: 10.20959/wjpps20172-8609

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causes.[3]

Over 100 cancers affect humans.[2]

Many cancers can be prevented by not smoking,

maintaining a healthy weight, not drinking too much alcohol, eating plenty of vegetables,

fruits and whole grains, vaccination against certain infectious diseases, not eating too much

processed and red meat and avoiding too much sunlight exposure.[4][5]

Early detection

through screening is useful for cervical and colorectal cancer.[6]

The benefits of screening in

breast cancer are controversial.[6][7]

Cancer is often treated with some combination

of radiation therapy, surgery, chemotherapy, and targeted therapy.[8]

Nanoparticles

The term "nanoparticle" is not usually applied to individual molecules; it usually refers to

inorganic materials.

The reason for the synonymous definition of nanoparticles and ultrafine particles is that,

during the 1970s and 80s, when the first thorough fundamental studies with "nanoparticles"

were underway in the USA (by Granqvist and Buhrman)[9]

and Japan, (within an ERATO

Project)[10]

they were called "ultrafine particles" (UFP). However, during the 1990s before

the National Nanotechnology Initiative was launched in the USA, the new name,

"nanoparticle," had become more common (for example, see the same senior author's paper

20 years later addressing the same issue, lognormal distribution of sizes[11]

). Nanoparticles

can exhibit size-related properties significantly different from those of either fine particles or

bulk materials.[12][13]

Nanoclusters have at least one dimension between 1 and 10 nanometers and a narrow size

distribution. Nanopowders[14]

are agglomerates of ultrafine particles, nanoparticles, or

nanoclusters. Nanometer-sized single crystals, or single-domain ultrafine particles, are often

referred to as nanocrystals. Fig 1.[15]

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Types of nanoparticles

1. Inorganic particles

So far, there are different types of inorganic metals and metal oxide NPs, which have been

studied. Some important examples are detailed (Figure 2).

Gold nanoparticles

As compared to Ag, Au nanoparticles are less effective and lack antimicrobial properties

when used alone but found to be effective when used in combination with antibiotics such as

ampicillin[16,17]

, vancomycin[18]

and lysozyme (an antibacterial enzyme).[19]

The Au

nanoparticles can also be used in combination with nonantibiotic molecules such as amino

substituted pyrimidines[20]

and citrate, which induces the generation of ROS and mutations,

hence used in cancer therapy.[21]

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2. Organic Nanoparticles

Some of the well-known examples of organic NPs are discussed below (Figure 3).

Applications of nanoparticles

Antibacterial Activity

Algal-synthesized NPs are known to possess efficient antibacterial activity (Figure 4; Table

1). Brown alga (Bifurcaria bifurcate) is reported for the synthesis of copper oxide

nanoparticle (5–45 nm) exhibiting antibacterial activity against Enterobacter

aerogenes (Gram-negative) and S. aureus (Gram-positive).[22]

Gold nanoparticles synthesized

using Galaxaura elongata (powder or extract) were evaluated for their antibacterial activities

which showed better antibacterial effects against E. coli, K. pneumoniae, MRSA, S. aureus,

and Pseudomonas aeruginosa.[23]

In another work, silver chloride (AgCl) NPs synthesized

using marine alga Sargassum plagiophyllum were analyzed using fluorescence and electron

microscopy showed bactericidal activity against E. coli.[24]

Synthesis of AgNPs using fresh

extract and whole cell of microalga Chlorococcum humicola inhibited the growth of Gram-

negative bacteria E. coli (ATCC 1105).[25]

In a recent report, the aqueous extract of a

diatom Amphora-46 was used for the light-induced biosynthesis of polycrystalline AgNPs, in

which fucoxanthin a photosynthetic pigment was responsible for the reduction of Ag ion.

Furthermore, the synthesized AgNPs were tested against Gram-positive and Gram-negative

bacteria for its antibacterial activity.[26]

Fig 4.

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Antibiofilm activity of different NPs against microbial pathogen. [Table 1]

Nanoparticle Target organism References

Silver nanoparticles S. paratyphi, P. aeruginosa, S.

epidermidis [27,28]

Bismuth oxide aqueous colloidal

nanoparticles C. albicans, S. mutans

[29,30]

Nano-oil formulation from Mentha

piperita L Staphylococcus sp.

[31]

Nano-emulsion (detergent, oil, and

water) in combination with

cetylpyridinium chloride

A. baumannii [32]

Silver- and gold-incorporated

polyurethane, polycaprolactam,

polycarbonate, and

polymethylmethacrylate

E. coli [33]

Silver nanoparticles in combination

with nystatin and chlorhexidine C. albicans, C. glabrata

[34]

Silver nanoparticle and 12-

methacryloyloxydodecylpyridinium

bromide (MDPB)

Dental plaque microcosm

biofilms [35,36]

Copper P. aeruginosa [37]

Zinc Actinobacillus

pleuropneumoniae, S. [38]

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Nanoparticle Target organism References

Typhimurium, Haemophilus

parasuis, E. coli, S. aureus, S.

suis

Magnetite nanoparticles C. albicans [39]

Eugenia carryophyllata essential oil

stabilized by iron

oxide/oleic acid core/shell

nanostructures

S. aureus [40,41]

Zinc and copper oxide nanoparticles S. mutans [42]

Zerovalent bismuth nanoparticle S. mutans [43]

Dextran sulfate nanoparticle complex

containing ofloxacin and levofloxacin P. aeruginosa

[44]

PEG-stabilized lipid nanoparticles

loaded with terpinen-4-ol C. albicans

[45]

Magnesium fluoride nanoparticles S. aureus, E. coli [46,47]

Yttrium fluoride nanoparticles S. aureus, E. coli [48]

Iron oxide/oleic acid in combination

with essential oil from Rosmarinus

officinalis

C. albicans, C. tropicalis [49]

Gold nanoparticles and methylene blue C. albicans [50]

Starch-stabilized silver nanoparticles S. aureus, P. aeruginosa [51]

Iron oxide–oleic acid nanofluid S. aureus [52]

Quaternary ammonium

polyethylenimine nanoparticles Oral biofilms

[53]

Zinc oxide nanoparticles, chitosan

nanoparticles and combination of both E. faecalis

[54]

Polyurethane nanocomposite S. epidermidis [55]

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The aqueous extract of red marine algae Gracilaria corticata as the reducing agent was

explored for its antibacterial activity against Gram-positive and Gram-negative bacteria.[56]

U.

fasciata-based AgNPs were synthesized and used to inhibit the growth of Xanthomonas

campestris pv. Malvacearum.[57]

Another work shows the antibacterial activity of AuNPs

synthesized using marine brown algae Turbinaria conoides, against Streptococcus sp., B.

subtilis and K. pneumonia.[58]

Ag, Au and bimetallic alloy Ag–Au nanoparticles were

synthesized from marine red alga, Gracilaria sp., exhibited good antibacterial activity against

Gram-positive bacteria S. aureus and Gram-negative bacteria K. pneumonia.[59]

Extracellular

synthesis of AgNPs from the thallus broth of marine algae Padina pavonica (Linn.) inhibited

the growth of cotton Fusarium wilts (Fusarium oxysporum f. sp. vasinfectum) and bacterial

leaf blight (Xanthomonas campestris pv. malvacearum).[60]

Bactericidal activity of AgNPs

and nanocomposite material synthesized using agar extracted from the red alga Gracilaria

dura was tested against B. pumilus (accession number HQ318731).[61]

In a work done by

Suganya et al.[62]

Blue green alga S. platensis protein mediated synthesis of AuNPs was

performed; further, it showed efficient antibacterial activity against Gram-positive bacteria

(B. subtilis and S. aureus).

Gold nanoparticles

Common oxidation states of gold include +1 (Au [I] or aurous compounds) and +3 (Au [III]

or auric compounds). GNPs, however, exist in a non-oxidised state (Au [0]). GNPs are not

new; in the 19th century, Michael Faraday[63]

published the first scientific paper on GNP

synthesis, describing the production of colloidal gold by the reduction of aurochloric acid by

phosphorous. In the late 20th century, techniques including transmission electron microscopy

(TEM) and atomic force microscopy (AFM) enabled direct imaging of GNPs and control of

properties such as size and surface coating was refined.[64]

Common methods of GNP

production include citrate reduction of Au [III] derivatives such as aurochloric acid (HAuCl4)

in water to Au (0) and the Brust–Schiffrin method, which uses two-phase synthesis and

stabilisation by thiols.[65,66]

In recent years there has been an explosion in GNP research, with

a rapid increase in GNP publications in diverse fields including imaging, bioengineering and

molecular biology (Figure 5). It is probable that this relates to a similar increase in the

broader field of nanotechnology, increased governmental awareness and funding, and rapid

progress in chemical synthesis and molecular biology.[67]

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Figure 5

Number of gold nanoparticle papers published each year. Source: ISI Web of Knowledge.

Available from: www.webofknowledge.com.

GNPs exhibit unique physicochemical properties including surface plasmon resonance (SPR)

and the ability to bind amine and thiol groups, allowing surface modification and use in

biomedical applications.[68]

Nanoparticle functionalisation is the subject of intense research at

present, with rapid progress being made towards the development of biocompatible,

multifunctional particles for use in cancer diagnosis and therapy.[69]

For example, a

multifunctional micellar hybrid nanoparticle containing metal nanoparticles for MRI

detection, quantum dots for near infrared fluorescent imaging, polyethylene glycol (PEG) to

increase circulation times, the tumour-specific F3 peptide for targeting and doxorubicin as a

therapeutic payload has recently been developed. Efficacy has been demonstrated in

vitro and in vivo in a mouse model implanted with human breast cancer cells.[70]

There has been considerable debate about the mode of entry of GNPs into cells, with the most

likely mechanism being non-specific receptor mediated endocytosis (RME).[71]

In vivo, even

in the absence of functionalisation, nanoparticles passively accumulate at tumour sites that

have leaky, immature vasculature with wider fenestrations than normal mature blood

vessels.[72]

This is known as the enhanced permeability and retention (EPR) effect.

Difficulties in utilising the EPR effect for tumour drug delivery exist owing to the

heterogeneity of tumour vasculature, particularly at the centre of poorly differentiated

cancers, as well as particle detection and uptake by the reticuloendothelial system (RES).[73]

PEGylation is the most common method of reducing RES uptake, producing a hydrated

barrier causing steric hindrance to the attachment of phagocytes.[74]

The EPR effect combined

with longer circulation times, often achieved by PEGylation, can increase concentrations of

drug in tumours by 10–100-fold compared with the use of free drugs.[75]

Further 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

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nanoparticles.[76,77,78]

Toxicity studies of GNPs have been conflicting, with interactions

between GNPs and tissue at the cellular, intracellular and molecular levels remaining poorly

understood.[79]

While some studies have shown no cellular toxicity, other in vitro and in

vivo studies have demonstrated cellular reactive oxygen species production, mitochondrial

toxicity, cytokine release, apoptosis and necrosis.[80,81-87]

Nanotechnology

The concept of nanotechnology began in 1959 [Fig -6], when Richard Feynman first

proposed the principle that devices and materials could one day be constructed to atomic

detailing. In his reputable speech ―There’s plenty of room at the bottom‖ he addresses the

problem of controlling and manipulating objects on a miniscule scale.[88]

His thoughts and

hypothesis were the grounding for what was and is the nano- revolution. Nanotechnology

deals with structures that are of 100 nanometres or smaller. The majority of animal cells are

approximately 7,000 to 20,000 nanometres in width. Therefore, it would be ideal for nano

tools to be used to interact with the structures within a cell such as the DNA and proteins.

The following diagram illustrates the relative sizes of nanoparticles[89]

Materials reduced to

the nanoscale can show different properties compared to what they exhibit on a macroscale,

enabling unique applications. A material such as gold for example, which is chemically inert

at normal scales, can become a potent chemical catalyst at nanoscales. Much of the interest in

nanotechnology stems from such quantum and surface phenomena that matter exhibits at the

nanoscale.

Fig 6

The process of nanotechnology which inhibit cancerous cells is shown in Fig 7.

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Impacts on Cancer[90]

Biological processes, including ones necessary for life and those that lead to cancer, occur at

the nanoscale. Thus, in fact, we are composed of a multitude of biological nano-machines.

Nanotechnology provides researchers with the opportunity to study and manipulate

macromolecules in real time and during the earliest stages of cancer progression.

Nanotechnology can provide rapid and sensitive detection of cancer-related molecules,

enabling scientists to detect molecular changes even when they occur only in a small

percentage of cells. Nanotechnology also has the potential to generate entirely novel and

highly effective therapeutic agents. Fig 8.

Benefits for Diagnosis[91]

Imaging

Current imaging methods can only readily detect cancers once they have made a visible

change to a tissue, by which time thousands of cells will have proliferated and perhaps

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metastasized. And even when visible, the nature of the tumor—malignant or benign—and the

characteristics that might make it responsive to a particular treatment must be assessed

through biopsies. Imagine instead if cancerous or even pre-cancerous cells could somehow be

tagged for detection by conventional scanning devices. Two things would be necessary—

something that specifically identifies a cancerous cell and something that enables it to be

seen—and both can be achieved through nanotechnology. For example, antibodies that

identify specific receptors found to be overexpressed in cancerous cells can be coated on to

nanoparticles such as metal oxides which produce a high contrast signal on Magnetic

Resonance Images (MRI) or Computed Tomography (CT) scans. Once inside the body, the

antibodies on these nanoparticles will bind selectively to cancerous cells, effectively lighting

them up for the scanner. Similarly, gold particles could be used to enhance light scattering for

endoscopic techniques like colonoscopies. Nanotechnology will enable the visualization of

molecular markers that identify specific stages and types of cancers, allowing doctors to see

cells and molecules undetectable through conventional imaging.

Screening

Screening for biomarkers in tissues and fluids for diagnosis will also be enhanced and

potentially revolutionized by nanotechnology. Individual cancers differ from each other and

from normal cells by changes in the expression and distribution of tens to hundreds of

molecules. As therapeutics advance, it may require the simultaneous detection of several

biomarkers to identify a cancer for treatment selection. Nanoparticles such as quantum dots,

which emit light of different colors depending on their size, could enable the simultaneous

detection of multiple markers. The photoluminescence signals from antibody-coated quantum

dots could be used to screen for certain types of cancer. Different colored quantum dots

would be attached to antibodies for cancer biomarkers to allow oncologists to discriminate

cancerous and healthy cells by the spectrum of light they see.

Benefits for Treatment and Clinical Outcomes[92]

Cancer therapies are currently limited to surgery, radiation, and chemotherapy. All three

methods risk damage to normal tissues or incomplete eradication of the cancer.

Nanotechnology offers the means to aim therapies directly and selectively at cancerous cells.

Nanocarriers

Conventional chemotherapy employs drugs that are known to kill cancer cells effectively.

But these cytotoxic drugs kill healthy cells in addition to tumor cells, leading to adverse side

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effects such as nausea, neuropathy, hair-loss, fatigue, and compromised immune function.

Nanoparticles can be used as drug carriers for chemotherapeutics to deliver medication

directly to the tumor while sparing healthy tissue. Nanocarriers have several advantages over

conventional chemotherapy. They can:

protect drugs from being degraded in the body before they reach their target.

enhance the absorption of drugs into tumors and into the cancerous cells themselves.

allow for better control over the timing and distribution of drugs to the tissue, making it

easier for oncologists to assess how well they work.

prevent drugs from interacting with normal cells, thus avoiding side effects.

Destruction from within

Moving away from conventional chemotherapeutic agents that activate normal molecular

mechanisms to induce cell death, researchers are exploring ways to physically destroy

cancerous cells from within. One such technology—nanoshells—is being used in the

laboratory to thermally destroy tumors from the inside. Nanoshells can be designed to absorb

light of different frequencies, generating heat (hyperthermia). Once the cancer cells take up

the nanoshells (via active targeting), scientists apply near-infrared light that is absorbed by

the nanoshells, creating an intense heat inside the tumor that selectively kills tumor cells

without disturbing neighbouring healthy cells. Similarly, new targeted magnetic nanoparticles

are in development that will both be visible through Magnetic Resonance Imaging (MRI) and

can also destroy cells by hyperthermia.

CONCLUSION

GNPs (Gold Nanoparticles) have many properties that are attractive for use in cancer therapy.

They are small and can penetrate widely throughout the body, preferentially accumulating at

tumour sites. Cancer therapies are currently limited to surgery, radiation and chemotherapy.

...Nanotechnology offers the means to aim therapies directly and selectively at cancerous

cells (Nanocarriers). Conventional chemotherapy employs drugs that are known to

kill cancer cells effectively. Nanotechnology is definitely a medical boon for diagnosis,

treatment and prevention of various diseases including cancer. It supports and expands the

scientific advances in genomic and proteomics and builds on our understanding of the

molecular underpinnings of cancer and its treatment.

While nanotechnology is seen as the way of the future and is a technology that a lot of people

think will bring a lot of benefit for all who will be using it, nothing is ever perfect and there

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will always be pros and cons to everything. The advantages and disadvantages of

nanotechnology can be easily enumerated and here are some of them.

Advantages and Disadvantages of Nanotechnology[93]

Advantages

ionize a lot of electronic products, procedures and

applications. The areas that benefit from the continued development of nanotechnology when

it comes to electronic products include nano transistors, nano diodes, OLED, plasma displays,

quantum computers, and many more.

energy-producing, energy-absorbing and energy storage products in smaller and more

efficient devices is possible with this technology. Such items like batteries, fuel cells and

solar cells can be built smaller but can be made to be more effective with this technology.

Disadvantages of Nanotechnology

When tackling the advantages and disadvantages of nanotechnology, you will also need to

point out what can be seen as the negative side of this technology:

Atomic weapons can now be more accessible and made to be more powerful and more

destructive. These can also become more accessible with nanotechnology.

Since these particles are very small, problems can actually arise from the inhalation of

these minute particles, much like the problems a person gets from inhaling minute

asbestos particles.

Presently, nanotechnology is very expensive and developing it can cost you a lot of

money. It is also pretty difficult to manufacture, which is probably why products made

with nanotechnology are more expensive.

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