Polymeric Nanoparticles for Cancer Gene Therapy

In cancer gene therapy, nucleic acids (DNA/RNA) are delivered to cancer cells (a method known as transfection) to either initiate the expression of harmful proteins that are able to kill them or to inhibit the function of crucial proteins in the cells. The lack of safe and effective carrier systems is a major barrier to the successful translation of cancer gene therapy to the clinic. The DNA/RNA carriers that are presently existing are restricted by issues such as immunogenicity and a lack of selectivity, that is, they can deliver genes to both tumour and normal cells [1,2]. A promising alternative for such carrier applications is cationic polymerbased nanoparticles [3]. These nanoparticles are formed through electrostatic interactions between anionic nucleic acids and cationic polymers. The nucleic acids encapsulated within nanoparticles are safeguarded against possible degradation in the circulatory system. In addition, nanoparticles also passively accumulate in tumors, rather than in healthy tissues. This passive tumour targeting phenomenon has the ability to reduce non-specific dissemination while preserving on-target effectiveness. However, macrophages, a particular form of immune cell which is responsible for removing cellular debris and infectious agents, can easily eliminate several nanoparticle systems from circulatory system.


Introduction
In cancer gene therapy, nucleic acids (DNA/RNA) are delivered to cancer cells (a method known as transfection) to either initiate the expression of harmful proteins that are able to kill them or to inhibit the function of crucial proteins in the cells. The lack of safe and effective carrier systems is a major barrier to the successful translation of cancer gene therapy to the clinic. The DNA/RNA carriers that are presently existing are restricted by issues such as immunogenicity and a lack of selectivity, that is, they can deliver genes to both tumour and normal cells [1,2]. A promising alternative for such carrier applications is cationic polymerbased nanoparticles [3]. These nanoparticles are formed through electrostatic interactions between anionic nucleic acids and cationic polymers. The nucleic acids encapsulated within nanoparticles are safeguarded against possible degradation in the circulatory system.
In addition, nanoparticles also passively accumulate in tumors, rather than in healthy tissues. This passive tumour targeting phenomenon has the ability to reduce non-specific dissemination while preserving on-target effectiveness. However, macrophages, a particular form of immune cell which is responsible for removing cellular debris and infectious agents, can easily eliminate several nanoparticle systems from circulatory system. Therefore, vital organs with a large population of resident macrophages (such as the liver and lungs) often show a high degree of non-specific nanoparticle aggregation. As a result, nontarget delivery of nucleic acids is still a major concern with cationic nanoparticles and enhancing targeting efficacy is a key problem for cancer gene therapy [4]. To overcome these issues recently various groups have developed functionalized polymers through the conjugation of targeting ligands (aptamer, peptide, lipids, small molecule and antibody/antibody fragment etc.) for delivering DNA/ RNA to tumour sites effectively. Polymeric nanoparticle platforms are characterized by their unique physicochemical structures, including polymeric micelle, solid polymeric nanoparticles, polymer conjugate, polymer some, dendrimer, polyplex, and polymer-lipid hybrid system. This mini review will cover the natural and synthetic polymers used to make nanoparticles for the delivery of genes to tumor sites (Table 1).

ARTICLE INFO ABSTRACT
Developments in biomaterials have driven enhancements to nanoparticle stability and tissue targeting, conjugation of ligands to the surface of polymeric nanoparticles enable binding to specific tumor cells, and the design of transcriptional elements has enabled selective DNA/RNA expression specific to the tumor cells. Collectively, these characteristics have enhanced the performance of polymeric nanoparticles as targeted non-viral gene delivery vectors for cancer treatment. Since polymeric nanoparticles are biodegradable, non-toxic, and to have reduced immunogenicity and tumorigenicity compared to viral vectors, they have substantial therapeutic potential for clinical use. In this article, various natural and synthetic polymers used in designing polymeric nanoparticles for targeted cancer gene therapy are reviewed.

Polymers used in the Preparation of Nanoparticles
Various materials are available for the preparation of nanoparticles such as polymers, lipids and inorganic metals (gold, silver, silicon, platinum etc.). Nature has also designed nanosized particles, specifically viruses for tissue-specific targeting and imaging agents in vivo [5]. Due to their stability, gene loading applications. It is biodegradable, non-toxic, inexpensive, readily available, and has been found to be a mucoadhesive, biocompatible, and non-immunogenic substance. Specifically, the simple aqueousbased gel formation of sodium alginate in the presence of divalent cations such as Ca2+ has been used for gene delivery [9]. Alginate based nanoparticulate delivery system was developed for frontline ATDs (Rifampicin, Isoniazid, Pyrazinamide and Ethambutol).

Chitosan: Chitosan is a modified natural cationic polysaccharide
prepared by chemical deacetylation of chitin, the second most abundant natural biopolymer after cellulose that is derived from crustacean shells [10]. The primary amino groups in the polymer backbone of chitosan provide positive charge on its surface. Due to its structure and physical, chemical and biological properties like easily modifiable, nontoxicity and adhesivity chitosan has been regarded as a potential gene carrier in the gastrointestinal tract. Another important feature of using chitosan as gene carrier is its metabolic degradation in the body. In addition, chitosan also provides easy elimination process after gene administration, It can also be used as a diluent/ filler in the gene delivery systems [11]. Chitosan has many potential applications in gene delivery via the oral, nasal, transdermal, parenteral, vaginal, cervical and rectal routes [12]. in tissue engineering research [15].

Poly-ε-caprolactone (PCL):
Poly-ε-Caprolactone (PCL) is a synthetic aliphatic polyester which has received great attention worldwide for use in gene delivery systems. It is biocompatible, biodegradable and hydrophobic (water insoluble) polymer suitable for gene delivery carrier due to a high permeability to many hydrophobic drugs and at the same time being free from toxicity.
It can form compatible blends with other polymers. Owing to its slow biodegradation it is ideally suitable for long-term delivery extending over a period of more than one year. Several genes have been encapsulated in PCL for targeted gene delivery [16,17].

Conclusion
Polymeric nanoparticle-based cancer gene therapy is still in its early stages at the clinical trials but has a bright future. Polymeric nanoparticle-based approaches to gene therapy have lagged in transfection efficacy relative to viral vector-based gene therapies, but they have enhanced safety, lower risks of immunogenicity and tumorigenesis, improved manufacturing and quality control, enhanced targeting capabilities, and far greater nucleic acid carrying ability. With developments in transfection efficacy and tumor specificity through various targeting approaches, polymeric nanoparticle-based gene therapy has a promising future.