Elsevier

Advanced Drug Delivery Reviews

Volume 66, February 2014, Pages 110-116
Advanced Drug Delivery Reviews

Liposomal siRNA nanocarriers for cancer therapy

https://doi.org/10.1016/j.addr.2013.12.008Get rights and content

Abstract

Small interfering RNAs (siRNA) have recently emerged as a new class of therapeutics with a great potential to revolutionize the treatment of cancer and other diseases. A specifically designed siRNA binds and induces post-transcriptional silencing of target genes (mRNA). Clinical applications of siRNA-based therapeutics have been limited by their rapid degradation, poor cellular uptake, and rapid renal clearance following systemic administration. A variety of synthetic and natural nanoparticles composed of lipids, polymers, and metals have been developed for siRNA delivery, with different efficacy and safety profiles. Liposomal nanoparticles have proven effective in delivering siRNA into tumor tissues by improving stability and bioavailability. While providing high transfection efficiency and a capacity to form complexes with negatively charged siRNA, cationic lipids/liposomes are highly toxic. Negatively charged liposomes, on the other hand, are rapidly cleared from circulation. To overcome these problems we developed highly safe and effective neutral lipid-based nanoliposomes that provide robust gene silencing in tumors following systemic (intravenous) administration. This delivery system demonstrated remarkable antitumor efficacy in various orthotopic human cancer models in animals. Here, we briefly overview this and other lipid-based approaches with preclinical applications in different tumor models for cancer therapy and potential applications as siRNA-nanotherapeutics in human cancers.

Introduction

The discovery of RNA interference (RNAi), including micro RNA (miRNA) and small-interfering RNA (siRNA) mediated gene silencing, is considered one of the most important advancements in biology in the last decade [1], [2], [3]. siRNA is now commonly used as a powerful tool for silencing post-transcriptional gene expression and investigating gene. More importantly, potential applications of siRNA have led to a great interest in harnessing this technology for therapeutic use in cancer and other diseases. A specifically designed siRNA can bind the target gene (mRNA) in a sequence specific manner and induce degradation of mRNA translation [3]. These short double-stranded (ds) RNAs are cleaved into fragments called siRNA (21-base pairs) by DICER protein. The target mRNA is bound by the antisense strand after forming a complex with proteins, designated as the RNA-Induced Silencing Complex (RISC). An RNA endonuclease (Argonaute 2) within the complex cleaves the target mRNA and leads to its degradation, shutting down protein expression (Fig. 1). For therapeutic applications, synthetic siRNA is used for targeting oncogenes and genes that are involved in cancer cell proliferation, survival, invasion, angiogenesis, metastasis, and resistance to chemotherapy or radiotherapy in cancer and for targeting disease-causing genes in other pathologies [4], [5].

The broad therapeutic applications of siRNA-based therapeutics in cancer are largely dependent on the development of rationally designed systemic delivery systems that can efficiently deliver the siRNA molecules into tumors and target cells [6], [7]. The major limitations of the systemic use of siRNA-based therapies include rapid degradation by nucleases (half-life ~ 15 min in serum) and renal clearance following systemic administration [8]. Thus earlier studies with siRNA-based therapies entered into clinical trials relied on the local administration, including the intravitreal or intranasal routes [7], [8]. To enhance the stability of various siRNA chemical modifications, such as backbone (phosphorothioate, boranophosphate) and sugar modifications (2′ modifications to the sugar ring, namely 2′-OMe, 2′-fluoro, and 2′-O-methoxyethyl (2′-MOE)), have been used [7]. However, poor cellular uptake remains an important issue due to negatively charged cell membranes preventing efficient intracellular uptake of siRNA molecules, which also have a negatively charged backbone, leading to electrostatic repulsion, requiring a carrier to increase the uptake into cancer cells. Rationally designed specific siRNA for the exclusion of partially complementary sequences and certain motifs that induce immune response and the use of the minimum effective dose of siRNA may also enhance unwanted side effects [4]. Overall, developments of safe, stable, effective and tumor-specific delivery systems for systemic administration are important goals for translation of siRNA-based therapeutics into successful clinical applications. Nanotechnology holds promise for widespread clinical applications of siRNA-therapeutics. Nanocarriers also have great potential to reduce siRNA related toxicities and prevent off-target effects in normal tissues (reviewed in detail by Jackson and Linsley, 2010) [50].

Section snippets

Nanocarriers for systemic siRNA delivery

Nanocarriers (submicron size particles ranging from 1 to 1000 nm) can overcome most hurdles that prevent the systemic use of siRNA [9], [10]. Nanoparticles have been shown to carry and deliver desired cargos or payloads, such as chemotherapeutic agents, oligonucleotides, drugs, peptides, and imaging agents in in vivo systems. In general, the ideal nanocarrier is expected to be safe, non-toxic, biocompatible, biodegradable, and non-immunogenic, and to be able to bypass rapid hepatic or renal

Clinical applications of siRNA-nanotherapeutics

siRNA-based therapies have quickly moved into the clinic especially for diseases requiring localized or topical delivery, including age-related macular degeneration, diabetic macular edema, and respiratory virus infection and pachyonychia congenital [7]. The first clinical trial involving siRNA began in 2004 for the treatment of acute macular degeneration [6]. Later, several clinical trials based on systemic delivery of siRNA-therapies have progressed into the clinic and are currently being

Tumor-targeting nanoparticles

Targeted delivery (active delivery) of therapeutics and diagnostics into tumor cells and/or tumor-vasculature is recognized as a powerful approach for treatment of cancer. Targeted drug delivery systems expand the therapeutic windows of drugs by increasing delivery to the target tissue and reducing side-effects. Traditionally, this concept was proven to work by using tumor cell specific antibodies [37]. Tumor-targeting nanocarriers can accumulate in tumor tissues (about 10–100 fold) compared

Conclusion and future prospects

Nanocarriers hold great potential for cancer therapy, diagnosis and imaging. In addition to the delivery of wide variety of anti-cancer agents, they seem to be the best candidates for the administration of siRNA-based therapeutics and are currently being tested in human clinical trials. Pharmacokinetic, pharmacodynamic parameters and most importantly the toxicity/safety profiles of various potential siRNA delivery systems should be well defined and considered in future studies to develop highly

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    This review is part of the Advanced Drug Delivery Reviews theme issue on “Cancer Nanotechnology”.

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