Delivery strategies and potential targets for siRNA in major cancer types☆
Graphical abstract
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.
References (217)
- et al.
Structural insights into RNA interference
Curr. Opin. Struct. Biol.
(2010) - et al.
Single-stranded antisense siRNAs guide target RNA cleavage in RNAi
Cell
(2002) - et al.
Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease
Cell
(2010) - et al.
A review of the current status of siRNA nanomedicines in the treatment of cancer
Biomaterials
(2013) - et al.
Evaluation of the safety, tolerability and pharmacokinetics of ALN-RSV01, a novel RNAi antiviral therapeutic directed against respiratory syncytial virus (RSV)
Antivir. Res.
(2008) Progress towards in vivo use of siRNAs
Mol. Ther.
(2006)- et al.
Structural modification of siRNA for efficient gene silencing
Biotechnol. Adv.
(2013) - et al.
LNA: a versatile tool for therapeutics and genomics
Trends Biotechnol.
(2003) - et al.
Biodistribution of phosphodiester and phosphorothioate siRNA
Bioorg. Med. Chem. Lett.
(2004) - et al.
Biocompatible gelatin nanoparticles for tumor-targeted delivery of polymerized siRNA in tumor-bearing mice
J. Control. Release
(2013)
Stability and cellular uptake of polymerized siRNA (poly-siRNA)/polyethylenimine (PEI) complexes for efficient gene silencing
J. Control. Release
Self-crosslinked human serum albumin nanocarriers for systemic delivery of polymerized siRNA to tumors
Biomaterials
Bioreducible hyaluronic acid conjugates as siRNA carrier for tumor targeting
J. Control. Release
Chemically modified siRNA: tools and applications
Drug Discov. Today
Atelocollagen-mediated systemic delivery prevents immunostimulatory adverse effects of siRNA in mammals
Mol. Ther.
Self-assembled siRNA-PLGA conjugate micelles for gene silencing
J. Control. Release
Systemic and specific delivery of small interfering RNAs to the liver mediated by apolipoprotein A-I
Mol. Ther.
Targeting cancer cells with nucleic acid aptamers
Trends Biotechnol.
Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship
Mayo Clin. Proc.
Enhanced intrapulmonary delivery of anticancer siRNA for lung cancer therapy using cationic ethylphosphocholine-based nanolipoplexes
Mol. Ther.
Pulmonary delivery of therapeutic siRNA
Adv. Drug Deliv. Rev.
siRNA delivery to the lung: what's new?
Adv. Drug Deliv. Rev.
Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
FEBS Lett.
Induction of apoptosis in non-small cell lung cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPA/siRNA complex nanoparticles
Biomaterials
Hepatitis C virus-induced hepatocarcinogenesis
J. Hepatol.
Liver as a target for oligonucleotide therapeutics
J. Hepatol.
The role of histone deacetylases (HDACs) in human cancer
Mol. Oncol.
HDAC2: a critical factor in health and disease
Trends Pharmacol. Sci.
RNA interference in the clinic: challenges and future directions
Nat. Rev. Cancer
Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles
Nature
Mechanisms of gene silencing by double-stranded RNA
Nature
RNAi therapeutics: a potential new class of pharmaceutical drugs
Nat. Chem. Biol.
Utilizing RNA interference to enhance cancer drug discovery
Nat. Rev. Drug Discov.
Synergetic regulatory networks mediated by oncogene-driven microRNAs and transcription factors in serous ovarian cancer
Mol. BioSyst.
Targeted therapies: time to shift the burden of proof for oncogene-positive cancer?
Nat. Rev. Clin. Oncol.
New approaches to molecular cancer therapeutics
Nat. Chem. Biol.
Interfering with disease: a progress report on siRNA-based therapeutics
Nat. Rev. Drug Discov.
On future's doorstep: RNA interference and the pharmacopeia of tomorrow
J. Clin. Invest.
Strategies for silencing human disease using RNA interference
Nat. Rev. Genet.
Nonviral in vivo delivery of therapeutic small interfering RNAs
Curr. Opin. Mol. Ther.
Position-specific chemical modification of siRNAs reduces “off-target” transcript silencing
RNA
Activation of the mammalian immune system by siRNAs
Nat. Biotechnol.
Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs
Nature
Fully 2′-deoxy-2′-fluoro substituted nucleic acids induce RNA interference in mammalian cell culture
Chem. Biol. Drug Des.
siRNA relieves chronic neuropathic pain
Nucleic Acids Res.
Uniformly modified 2′-deoxy-2′-fluoro phosphorothioate oligonucleotides as nuclease-resistant antisense compounds with high affinity and specificity for RNA targets
J. Med. Chem.
RNA interference in mammalian cells by chemically-modified RNA
Biochemistry
Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs
Nat. Biotechnol.
Tumor-homing poly-siRNA/glycol chitosan self-cross-linked nanoparticles for systemic siRNA delivery in cancer treatment
Angew. Chem.
Tumor-targeting transferrin nanoparticles for systemic polymerized siRNA delivery in tumor-bearing mice
Bioconjug. Chem.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “RNAi clinical translation”.
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These authors contributed equally.