Gold Nanoparticles; Breast Cancer Gene Therapy

MISBAH AKRAM

INTRODUCTION

Malignant word comes from Latin means “born to be bad”

Cells become cancer cells because of damage to DNA

No matter where a cancer may spread, it is always named for the place where it started

BREAST CANCER

Breast cancer is a heterogenous group of tumors with variable morphology, behavior, response to therapy and molecular profiles.

22.9% of all cancers in women In 2008, breast cancer caused 458,503 deaths worldwide Majority of breast cancer patients continue to be diagnosed at

a relatively late stage

BREAST CANCER IN PAK

Leading reported cancers

According to annual report of Shaukat Khanum Memorial Cancer Hospital & Research Centre in 2011 breast cancer accounts for 21.09% patients

CANCER GENE THERAPY

Gene therapy provides a novel platform for therapeutic intervention of several genetic and non-genetic disorders. The vast majority (81.5%) of gene therapy clinical trials to date has addressed cancer, cardiovascular disease and inherited monogenic diseases.

CANCER GENE THERAPY

A range of strategies has been applied to treat cancer, from inserting tumor suppressor genes:

to immunotherapy, oncolytic virotherapy gene directed enzyme pro-drug therapy

The p53 gene is by far the most commonly transferred tumor suppressor

gene, although others such as BRCA-1, Fus-1 and endostatin have been

used in cancer trials.

RNA INTERFERENCE

Inhibition of breast-cancer oncogenes results in induction of apoptosis and an increase of chemotherapy sensitivity in breast-cancer cells.

RNA interference (RNAi) provides an exemplary therapeutic model for treatment of cancer and other diseases.

NANOTECHNOLOGY

Nanotechnology is the use of materials on very small scales as in the cancer treatments that lies between 1 and 100 nm.

Nanoparticle can be nanosphere or nanocapsules.

In nanosphere drug is spread all over the particle while nanocapsule is hollow sphere in which drug is filled.

NANOPARTICLES

Some nanoparticles are coated with a polymeric layer of polyethylene glycol (PEG), some are liposomal,

polymer–drug conjugates, and some are Dendrimer, Polymerosome, Inorganic (Iron, silica, or quantum

dot core), Protein Carriers, Biological Nanoparticles, Hybrid Nanoparticles and micelle formed.

Nanoparticles exhibit unique pharmacokinetics, have high surface-to-volume ratios, and may be

constructed from a wide range of materials, because of these properties nanoparticles have got priority

over other therapies.

Nanoparticles are more specific than traditional cancer medicines because of their targeted localization in

cancer cell and vigorous cellular uptake.

NANOPARTICLES

One of the first FDA approved Nano medicine, Doxil© which contains drug doxorubicin, used to treat ovarian

cancer and other myeloma.

In recent year Carbon nanotubes are also being use to deliver drug to the target site because of their specificity to

the cell, high compatibility and high carrying capacity, they are also use as imaging agent. But CBTs persist in body

for many days, weeks or even months this property make them less useful as compare to other therapies.

Nanoparticles are used in an extensive range of medical research and disease treatments. They are known to have

the potential to serve as carriers for a variety of drugs, peptides and different vaccines and have successfully

delivered these to the target cells. They can also be utilized for gene therapy.

NANOPARTICLES

They have the potential to act as probes for diagnostic and therapeutic purposes as in

imaging and delivery of drug and genes which can be used to play an important role in

medicine. It is a priority research area in nano-medicine.

The structure of a particular cancer also plays a role in targeting treatment as many

different antigens are overexpressed in different cancers. Thus they are ideally targeted

as they are used for identification purposes and can be easily targeted as they are not

expressed significantly in any other part of the body.

NANOTECHNOLOGY-BASED GENE THERAPY

In gene therapy specific exogenous genes are integrated into the tumour cell genome to produce a tumoricidal

effect, and are a developing area of vast research.

Traditionally viral vectors are used for the transfer of the corrected genes but they have some serious drawbacks as

there is high risk of inflammatory and immune responses in the host and have gene control and targeting issues and

the virus can recover and cause diseases in favourable conditions.

To overcome these issues, non-viral gene transfer techniques are being searched, liposome mediated cationic

polymers and nanotechnology have advantage over viral vectors as they can be administered repeatedly at a very

low cost and have less immune reactions as they are non-toxic.

NANOTECHNOLOGY-BASED GENE THERAPY

The physical properties of nanoparticles including their size, morphology, charge

density and colloidal stability are important for finding their efficacy as non-viral

vector for gene transfer.

A biodegradable nano-polymeric carrier is known to have efficiently transferred Akt1

small interference RNA that led to the silencing of Akt1 protein and thus reduced

cancer cell survival, their proliferation, malignancy and metastasis properties

GOLD NANOPARTICLES

Gold nanoparticles have a broad range of applications with well characterized electronic and physical properties due

to well-developed synthetic procedures. In addition, their surface chemistry is easy to modify.

These features have made gold nanoparticles one of the most widely used nano-materials for academic research.

Gold nanoparticles are produced in a liquid form by reduction method which causes Au3+ to be reduced to neutral

gold atoms, gradually the solution becomes supersaturated, and gold precipitates in the form of sub-nanometer

particles.

The rest of the gold atoms that form, stick to the existing particles, and if the solution is stirred enough, the particles

formed are uniform in size.

GOLD NANOPARTICLES

Gold nanoparticles are of interest as potential in vivo diagnostic and therapeutic agents, as X-ray contrast agents,

drug delivery vehicles and radiation enhancers.

They can be functionalized with various organic ligands to create organic-inorganic hybrids with advanced

functionality.

Gold nanoparticles are best for cancer therapy because of their multifunctional properties.

They show remarkable results in drug carrier, thermal therapy, as contrast agent, radio-sensitizers, and have been

used in clinical trials as well.

GNPs are very small, and have large penetration power, and most important, they can bind many proteins & drugs

and can be vigorously directed to cancer cells.

TYPES OF GOLD NANOPARTICLES

BIO-SYNTHESIS OF GOLD NANOPARTICLES

Gold nanoparticles can be synthesized biologically using Magnolia

kobus and Diopyros kaki leaf extracts, also mediated through coriander.

The biological synthesis of cationic gold nanoparticles using peanut

leaf extract is also reported.

Synthesis of gold nanoparticles has also been reported using aqueous

root extract of Morinda citrifolia.

GENE THERAPY IN BREAST CANCER

Heterogeneity is observed within and between patients in breast cancers.

Tumors with similar histopathological diagnostics can follow different clinical courses and exhibit different responses to

therapy.

These cancers are generally considered to result from the mutations in genes that regulate cell growth and differentiation.

Carcinogenesis process can be a result of loss of tumor suppressor gene functions, which normally acts as a negative

regulator of cell proliferation.

Tumor suppressor gene inactivates and confer certain advantages to growth that lead to tumor progression.

GENE THERAPY IN BREAST CANCER

As cancer cells undergo numerous genetic changes less anticancer drugs are targeted towards the

genetic alterations existing in the cancerous cells.

The knowledge of the genetic changes may be exploited for development of new therapeutics.

Genes inhibiting the tumor growth, promoting tumor cell apoptosis or those enhancing the

cytotoxicity of chemotherapy may be identified.

The genes that once silenced enhance the chemo-sensitivity of tumor cells can also be used as

targets for drugs that would selectively increase the cytotoxicity of chemotherapy.

GENE THERAPY IN BREAST CANCER

We can identify genes that are involved in specific biological processes through gene silencing by

RNAi, and gradually we have created siRNA libraries through knockdown procedures.

The information gathered thus may be exploited for further research and probing into carcinogenesis.

Signal transduction pathways can be traced for the identification of novel genes using RNAi.

Retroviral-based siRNA libraries targeting about one-third of the human genome have successfully

identified genes involved in p53-mediated cell cycle arrest and novel tumor suppressor pathways.

Recently, siRNA and shRNA screens in human cells have successfully identified genes that are

important for cell growth, apoptosis, chemoresistance, and chemosensitivity.

GOLD NANOPARTICLES ASSOCIATED GENE THERAPY USING siRNA

The delivery of siRNA for RNA interference to the target site has been a problem as they may be

introduced to the tumor site but the introduction into the tumor parenchyma has to be systematic.

Although challenging, the systematic introduction of siRNA into the target site is extensively studied.

The siRNAs have to be targeted to specific genes in the correct tissue in an effective manner without

losing its stability.

Lipid, polymer and nanoparticle based vehicles for the transfer of siRNAs have been developed and

tested in different animal models.

GOLD NANOPARTICLES ASSOCIATED GENE THERAPY USING siRNA

However, they exhibit problems such as toxicity, immune responses, gene control and

gene-targeting

Therefore new approaches were required that would improve the efficiency of this

therapeutic technology and minimize the problems faced with the conventional strategies.

These nanoshells consist of a silica core and a gold shell, designed so as to absorb specific

light wavelengths determined by the size of the core and shell layers.

FUTURE PROSPECTS

Generally, siRNA-based treatments have opened new windows for the therapy of cancer. However, biochemical

modifications of siRNAs have been and will continue to maximize their potency, reduce their off-target effects and

other adverse effects to speed up the translation of siRNA drugs from the laboratory trials to clinical applications.

Gold nanoparticles with enhanced and modifiable fluorescence can be developed to be used for imaging purposes

and direct a specific drug or peptide or a monoclolnal antibody to the target site with increased efficiency and

efficacy.

The size of the nanoparticles makes them easily accessible to the target site in addition to their physical and

chemical properties.

FUTURE PROSPECTS

Cell-based therapy offers a promising solution for the treatment of diseases and injuries that

conventional medicines and therapies cannot cure effectively, and thus comprises an encouraging

arena for future medical breakthroughs.

The development of an accurate and quantitative noninvasive cell tracking technique is a highly

challenging task that could help in evaluating the effectiveness of treatments.

Moreover, cell tracking could provide essential knowledge regarding the fundamental trafficking

patterns and poorly understood mechanisms underlying the success or failure of cell therapy.