Elsevier

Advanced Drug Delivery Reviews

Volume 104, 1 September 2016, Pages 2-15
Advanced Drug Delivery Reviews

Delivery strategies and potential targets for siRNA in major cancer types

https://doi.org/10.1016/j.addr.2016.05.010Get rights and content

Abstract

Small interfering RNA (siRNA) has gained attention as a potential therapeutic reagent due to its ability to inhibit specific genes in many genetic diseases. For many years, studies of siRNA have progressively advanced toward novel treatment strategies against cancer. Cancer is caused by various mutations in hundreds of genes including both proto-oncogenes and tumor suppressor genes. In order to develop siRNAs as therapeutic agents for cancer treatment, delivery strategies for siRNA must be carefully designed and potential gene targets carefully selected for optimal anti-cancer effects. In this review, various modifications and delivery strategies for siRNA delivery are discussed. In addition, we present current thinking on target gene selection in major tumor types.

Introduction

The discovery of RNA interference (RNAi) has opened doors that might introduce a novel therapeutic tool to the clinical setting [1]. For many decades, small molecules have been developed and utilized in cancer therapy; however, critical problems, such as undesirable toxicity against normal tissues due to a lack of selectivity, still remain today. Using RNAi as a therapeutic tool will allow targeting previously unreachable targets with its potential to silence the function of any cancer causing gene [2]. This unique advantage is made possible by utilizing the biological functions of double-stranded RNA molecules (dsRNA). Endogenous dsRNA is recognized by a ribonuclease protein, termed dicer, and cleaved into small double stranded fragments of 21 to 23 base pairs in length with 2-nucleotide overhangs at the 3′ ends. The cleaved products are referred to as small interfering RNAs (siRNAs). The siRNAs consist of a passenger strand and a guide strand, and are bound by an active protein complex called the RNA-induced silencing complex (RISC). After binding to RISC, the guide strand is directed to the target mRNA, which is cleaved between bases 10 and 11 relative to the 5′ end of the siRNA guide strand, by the cleavage enzyme argonaute-2. Thus, the process of mRNA translation can be interrupted by siRNA [3], [4], [5].

The therapeutic application of siRNA has the potential to treat various diseases including cancer [6], [7]. Cancer is a genetic disease caused by the generation of mutated genes within tumor cells; multiple gene mutations both activate disease driving oncogenes and inactivate tumor suppressor genes in cancer [8], [9], [10]. Small interfering RNAs that can inactivate specific cancer driving genes have shown great potential as novel cancer therapeutics. Several anti-cancer siRNA based drugs have entered clinical trials, and many are actively sought after in preclinical research [11], [12], [13].

Even though the usage of siRNA as therapy has shown promise in the treatment of cancer, many obstacles that hinder the ultimate functionality of siRNAs in the clinic remain to be solved [14], [15]. In order to make this therapy effective, the first and most crucial step is to ensure the delivery of siRNA to the tumor cells from the injection site. In practice, siRNAs face physiological and biological barriers that prevent their delivery to the active site when administered systemically [16], [17], [18]. These barriers include, but are not limited to, intravascular degradation, recognition by the immune system, renal clearance, impediments to tumor tissue penetration and uptake into tumor cells, endosomal escape once in tumor cells, and off-target effects [19], [20], [21]. Delivery formulations as well as chemical modification of siRNA are required to overcome these challenges and facilitate siRNAs in reaching their target cells [22]. Furthermore, selection of gene targets in cancer is also crucial in designing siRNA therapeutic strategies. Discoveries of mechanisms in cancer provide innovative targets for siRNA therapy that in many cases cannot be targeted with conventional drugs. However, the particular gene pool that drives cancer varies depending on the origins and types of the tumors. Thus, careful selection of gene targets according to their cancer type is essential in siRNA therapeutic strategies.

To summarize, target discovery in cancer leads to the selection of siRNA gene targets, followed by their incorporation of the siRNAs into suitable delivery systems that allow access to the desired sites. Once therapeutic effect is observed, further application in varying organs and tissues can be anticipated as shown in Fig. 1. This review examines current thoughts on the therapeutic potential of siRNA delivery strategies and the optimal targets for siRNA in major cancer types.

Section snippets

Strategies for siRNA based therapeutics

In order to activate the RNAi pathway, double stranded siRNA must travel through the bloodstream and gain access to the cytosol of target cells. The hydrophilic nature and large molecular weight of siRNAs prevent the molecules from diffusing across the cellular membrane into the cell; therefore, modifications to the nucleic acid and generation of clever delivery strategies are necessary for the creation of siRNA therapeutics.

Current targets for siRNA in cancer

Cancer occurs as a result of a series of gene mutations in a cell. Generally, a combination of activating mutations in so-called oncogenes and the loss of tumor suppressor genes lead to uncontrolled cell growth and blockage of natural apoptotic processes [62], [63]. Because many key gene mutations involved in driving cancer, also known as driver genes, have been identified [64], [65], it is easy to see that siRNA therapeutics could be effective in cancer treatment [66], [67]. A major advantage

Future prospects

Despite our ever-increasing knowledge of cancer, cancer is still the second leading cause of death, overall, and is predicted to become the leading killer as heart disease therapies improve. Thanks to a multitude of large scale sequencing efforts, numerous genetic alterations have been identified in tumors, opening the way for the generation of siRNA therapeutics targeting both the mutant genes and in lesions in cancer signaling pathways arising from these genetic defects. Small molecule or

Acknowledgments

This study was supported by Global Innovative Research Center (GiRC) project (2012K1A1A2A01055811) of the National Research Foundation of Korea, the Intramural Research Program (Global RNAi Carrier Initiative) of KIST, and a grant from the Women's Cancers Program of Dana-Farber Cancer Institute.

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