Review
An overview of current delivery systems in cancer gene therapy

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Abstract

The main objective in gene therapy is the development of efficient, non-toxic gene carriers that can encapsulate and deliver foreign genetic materials into specific cell types such as cancerous cells. During the past two decades, enormous research in the area of gene delivery has been conducted worldwide, in particular for cancer gene therapy application. Viral vectors are biological systems derived from naturally evolved viruses capable of transferring their genetic materials into the host cells. Many viruses including retrovirus, adenovirus, herpes simplex virus (HSV), adeno-associated virus (AAV) and pox virus have been modified to eliminate their toxicity and maintain their high gene transfer capability. The limitations associated with viral vectors, however, in terms of their safety, particularly immunogenicity, and in terms of their limited capacity of transgenic materials, have encouraged researchers to increasingly focus on non-viral vectors as an alternative to viral vectors. Non-viral vectors are generally cationic in nature. They include cationic polymers such as poly(ethylenimine) (PEI) and poly(l-lysine) (PLL), cationic peptides and cationic liposomes. The newly described liposomal preparation LPD (liposomes/protamine/DNA), for example, has shown superiority over conventional liposomes/DNA complexes (lipoplexes). Although non-viral vectors are less efficient than viral ones, they have the advantages of safety, simplicity of preparation and high gene encapsulation capability. This article reviews the most recent studies highlighting the advantages and the limitations of various types of gene delivery systems used in cancer gene therapy.

Introduction

Gene therapy has become the research focus for many laboratories in pharmacy, medicine, biochemistry and chemical engineering worldwide. However, the growing potential of gene therapy for both genetically based and infectious diseases will not achieve its goals until the issue of gene delivery has been resolved. During the past 15 years, more than 400 clinical studies in gene therapy have been evaluated; almost 70% of these studies are in the area of cancer gene therapy [1].

The main objective in gene therapy is successful in vivo transfer of the genetic materials to the targeted tissues. The aim from the delivery system varies according to the application. For example, prolonged and sustained expression is needed for treating diseases related to one gene dysfunction like hypercholesterolemia while short period of gene expression is sufficient for most cancer gene therapy strategies.

Due to the complex nature of cancer, many therapeutic genes were utilized to eliminate cancerous lesions. The development of cancer cells is associated with multiple alterations on the genetic level of these cells [2]. Oncogenes and tumor suppressor genes play a crucial role in cancer development. These two gene groups counterbalance each other. While tumor suppressor genes induce apoptosis (programmed cell death), oncogenes enhance cell proliferation. Therefore, apoptotic genes and anti-oncogenes can be efficiently utilized in cancer treatment. On the other hand, chemotherapy and gene therapy can be combined via suicide gene strategy. This strategy relies on the conversion of a non-toxic prodrug into its active cytotoxic metabolite within the cancerous cells. This conversion is mediated by a non-mammalian enzyme, which is over-expressed in the neoplastic cells as a result of a successful transfection with their genes [3], [4]. Cancer is also immunogenic in nature [5]; therefore, boosting the immune response against cancerous cells can be achieved via genes encoding for cytokines such as interleukin-12 (IL-12) gene widely used in cancer gene therapy [6], [7]. Regardless of the therapeutic strategy, the development of efficient and safe gene delivery systems remains the main challenge for gene therapy including its main application—cancer gene therapy.

Despite that naked DNA was used successfully when injected directly into the tumor [6], [8] or as DNA vaccines [9], [10], it is highly prone to tissue clearance and totally inefficient for systematic delivery [11]. Gene therapy vehicles can be categorized into two groups: biological and non-biological systems. Each group has its own advantages and limitations. Biological carries are viruses, which were naturally evolved to infect cells and transfer their genetic materials into the host cells. Both RNA and DNA viruses have been evaluated as possible gene carriers. Viruses used in gene therapy are modified in the laboratory to eliminate their pathogenicity and retain their high efficiency in gene transfer. They are, however, difficult to produce and toxic (in particular immunogenic), as well as having a limitation in terms of the size of the inserted genetic materials [12]. These limitations are less encountered in non-viral gene carriers namely cationic polymers, cationic peptides and cationic lipids (liposomes). Their efficiency, however, is less than that of their viral counterparts. In addition, physical properties such as size and zeta potential play a critical role in their efficiency. In either delivery system, selected modifications that can produce safe, efficient and targetable gene carriers are desirable.

The most commonly used gene delivery systems (viral and non-viral) for cancer treatment and the recent developments in this area are the focus of this article. Emphasis is placed on the structure of cationic liposomes and on the different liposomal-DNA complexes.

Section snippets

Retrovirus

Retrovirus carriers are developed by replacing the vital viral genes with therapeutic ones. The ability of retroviral vectors to successfully deliver foreign genetic materials was first described in 1981 [13], [14]. Retroviruses are small RNA viruses with DNA intermediate, which integrates into the host genome producing the viral proteins (gag, pol and env), which are removed when developing the gene delivery carrier. In a recent study, a retroviral vector was encapsulated with genetic segment

Non-biological gene delivery systems (non-viral vectors)

Non-viral systems are cationic in nature. They interact with negatively charged DNA through electrostatic interactions. The total charge, however, maintains a positive net value. This will enable the carrier of efficiently interacting with the negatively charged cell membranes and internalizes into the cell, which occurs mainly through the endocytosis pathway [70].

Closing remarks

Gene therapy for cancer is the main application of gene therapy. A good gene delivery formulation for cancer therapy should encapsulate and protect the nucleic acid materials, escape the endosomal degradation and specifically target the tumor site. Both viral and non-viral vectors were developed and evaluated for delivering therapeutic genes that can terminate cancer cells. In the past few years, many modifications to the current delivery systems and novel carrier systems have been developed to

Acknowledgements

I would like to thank Mr. Saleh Saleh for providing the drawings of Fig. 2.

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