Nanoscale Small Interfering RNA Delivery Systems For Personalized Cancer Therapy (original) (raw)
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Nanoparticle-based delivery of small interfering RNA: challenges for cancer therapy
International Journal of Nanomedicine, 2012
During recent decades there have been remarkable advances and profound changes in cancer therapy. Many therapeutic strategies learned at the bench, including monoclonal antibodies and small molecule inhibitors, have been used at the bedside, leading to important successes. One of the most important advances in biology has been the discovery that small interfering RNA (siRNA) is able to regulate the expression of genes, by a phenomenon known as RNA interference (RNAi). RNAi is one of the most rapidly growing fields of research in biology and therapeutics. Much research effort has gone into the application of this new discovery in the treatment of various diseases, including cancer. However, even though these molecules may have potential and strong utility, some limitations make their clinical application difficult, including delivery problems, side effects due to off-target actions, disturbance of physiological functions of the cellular machinery involved in gene silencing, and induction of the innate immune response. Many researchers have attempted to overcome these limitations and to improve the safety of potential RNAi-based therapeutics. Nanoparticles, which are nanostructured entities with tunable size, shape, and surface, as well as biological behavior, provide an ideal opportunity to modify current treatment regimens in a substantial way. These nanoparticles could be designed to surmount one or more of the barriers encountered by siRNA. Nanoparticle drug formulations afford the chance to improve drug bioavailability, exploiting superior tissue permeability, payload protection, and the "stealth" features of these entities. The main aims of this review are: to explain the siRNA mechanism with regard to potential applications in siRNA-based cancer therapy; to discuss the possible usefulness of nanoparticlebased delivery of certain molecules for overcoming present therapeutic limitations; to review the ongoing relevant clinical research with its pitfalls and promises; and to evaluate critically future perspectives and challenges in siRNA-based cancer therapy.
Nanoparticulate RNA delivery systems in cancer
Cancer Reports, 2020
Background: Drug delivery system is a common practice in cancer treatment. RNA interference-mediated post-transcriptional gene silencing holds promise as an approach to knockdown in the expression of target genes responsible for cancer cell growth and metastasis. RNA interference (RNAi) can be achieved by delivering small interfering RNA (siRNA) and short hairpin RNA (shRNA) to target cells. Since neither interfering RNAs can be delivered in naked form due to poor stability, an efficient delivery system is required that protects, guides, and delivers the siRNA and shRNA to target cells as part of cancer therapy (chemotherapy). Recent findings: In this review, a discussion is presented about the different types of drug delivery system used to deliver siRNA and shRNA, together with an overview of the potential benefits associated with this sophisticated biomolecular therapy. Improved understanding of the different approaches used in nanoparticle (NP) fabrication, along with an enhanced appreciation of the biochemical properties of siRNA/ shRNA, will assist in developing improved drug delivery strategies in basic and clinical research. Conclusion: These novel delivery techniques are able to solve the problems that form an inevitable part of delivering genes in more efficient manner and as part of more effective treatment protocols. The present review concludes that the nanoparticulate RNA delivery system has great possibility for cancer treatment along with several other proposed methods. Several NPs or nanocarriers are already in use, but the methods proposed here could fulfill the missing gap in cancer research. It is the future technology, which unravels the mystery of resolving genomic diseases that is, especially genomic instability and its signaling cascades.
Journal of Nanobiotechnology, 2013
Background: Small interfering RNA (siRNA) has attracted attention in the field of nucleic acid medicine as a RNA interference (RNAi) application that leads to gene silencing due to specific messenger RNA (mRNA) destruction. However, since siRNA is unstable in blood and unable to cross the cell membrane, encapsulation of siRNA into a carrier is required. Results: In this study, we used a carrier that combined Z HER2 -displaying bio-nanocapsule (derived from hepatitis B virus surface antigen) and liposomes in a complex in order to investigate the feasibility of effective and target-cell -specific RNAi applications. As a result, by observing RNAi only in HER2-expressing breast cancer cells, using our proposed methodology, we successfully demonstrated target-cell-specific delivery and effective function expression of siRNA.
RNAi Therapeutics: Current Status of Nanoncologic siRNA Delivery Systems
Journal of Bionanoscience, 2011
With the growing comprehensive understanding of antisense gene silencing and the mechanism of RNA interference (RNAi), small interfering RNA (siRNA) has gained tremendous attention as a putative therapeutic agent for cancer therapy and other diseases. Due to its inherent target specificity, siRNA has the potential to inhibit tumor cell proliferation, metastasis and retard tumor growth, all-the-while avoiding off-target and adverse effects that are commonly observed with conventional anti-cancer drugs. There are a few ongoing clinical trials using siRNA for cancer treatment and other diseases. However, to date, none have been approved by FDA. Crucial for clinical success, delivery reagents that promote cellular uptake of the siRNA, maintain its stability in the presence of nucleases and prevent potential immunogenicity in vivo are required. Therefore, in recent years, a wide range of siRNA delivery systems have been developed and evaluated. In this review, we describe the major strategies currently employed for siRNA delivery followed by a presentation of the most recent works using such a variety of delivery systems and carriers in different cancers.
siRNA-based Nanoparticles for Cancer Therapy: Hurdles and Hopes
In recent times, profound advances in therapeutic strategies for cancer therapy have been made. Most of these strategies including cationic polymers, small molecule inhibitors and monoclonal antibodies originating from the bench have resulted in successful translations to the bedside. One of these remarkable strategies was the potential of small interfering RNA (siRNA) to regulate gene expression by RNA interference (RNAi). An avalanche of research has indeed proven that RNAi is extremely essential in cancer therapeutics, as well as a myriad of diseases. Their potential as therapeutic platforms however carry some limitations including delivery challenges, potential side effects, disturbance of intrinsic gene silencing mechanisms, and induction of the innate immune response. Some attempts have been made to overcome these challenges in order to improve the efficacy of RNAi-based therapeutics. Nanostructured entities (nanoparticles) and their formulations provide immense opportunities to substantially alter the treatment regimens, i.e. improving drug bioavailability, improving tissue permeability, and improving payload integrity. The objectives of this article are to (a) explain siRNA mechanism in the context of cancer therapy; (b) highlight the usefulness of nanoparticles-based delivery, and (c) review the prospects and challenges of the ongoing siRNA-based clinical research.
Lipid nanoparticles for targeted siRNA delivery – going from bench to bedside
International Journal of Nanomedicine, 2016
This review covers the basic aspects of small interfering RNA delivery by lipid nanoparticles (LNPs) and elaborates on the current status of clinical trials for these systems. We briefly describe the roles of all LNP components and possible strategies for their improvement. We also focus on the current clinical trials using LNP-formulated RNA and the possible outcomes for therapy in the near future. Also, we present a critical analysis of selected clinical trials that reveals the common logic behind target selection. We address this review to a wide audience, especially to medical doctors who are interested in the application of RNA interference-based treatment platforms. We anticipate that this review may spark interest in this particular audience and generate new ideas in target selection for the disorders they are dealing with.
Lipid nanoparticle delivery systems for siRNA-based therapeutics
Drug delivery and translational research, 2014
Therapeutics based on small interfering RNA (siRNA) have a huge potential for the treatment of disease but requires sophisticated delivery systems for in vivo applications. Lipid nanoparticles (LNP) are proven delivery systems for conventional small molecule drugs with over eight approved LNP drugs. Experience gained in the clinical development of LNP for the delivery of small molecules, combined with an understanding of the physical properties of lipids, can be applied to design LNP systems for in vivo delivery of siRNA. In particular, cationic lipids are required to achieve efficient encapsulation of oligonucleotides; however, the presence of a charge on LNP systems can result in toxic side effects and rapid clearance from the circulation. To address these problems, we have developed ionizable cationic lipids with pKa values below 7 that allow oligonucleotide encapsulation at low pH (e.g., pH 4) and a relatively neutral surface at physiological pH. Further optimization of cationic...
Small interfering RNAs (siRNAs) in cancer therapy: a nano-based approach
Cancer is one of the most complex diseases that has resulted in multiple genetic disorders and cellular abnormalities. Globally, cancer is the most common health concern disease that is affecting human beings. Great efforts have been made over the past decades in biology with the aim of searching novel and more efficient tools in therapy. Thus, small interfering RNAs (siRNAs) have been considered one of the most noteworthy developments which are able to regulate gene expression following a process known as RNA interference (RNAi). RNAi is a post-transcriptional mechanism that involves the inhibition of gene expression through promoting cleavage on a specific area of a target messenger RNA (mRNA). This technology has shown promising therapeutic results for a good number of diseases, especially in cancer. However, siRNA therapeutics have to face important drawbacks in therapy including stability and successful siRNA delivery in vivo. In this regard, the development of effective siRNA delivery systems has helped addressing these issues by opening novel therapeutic windows which have allowed to build up important advances in Nanomedicine. In this review, we discuss the progress of siRNA therapy as well as its medical application via nanoparticle-mediated delivery for cancer treatment.
Recent Targeted of siRNA Delivery Vehicles for Cancer Therapy
Biomedical Journal of Scientific & Technical Research, 2021
Recent progress in RNA biology has broadened the scope of therapeutic targets of RNA drugs for cancer therapy. However, RNA drugs, typically small interfering RNAs (siRNAs), are rapidly degraded by RNases and filtrated in the kidney, thereby requiring a delivery vehicle for efficient transport to the target cells. To date, various delivery formulations have been developed from cationic lipids, polymers, and/or inorganic nanoparticles for systemic delivery of siRNA to solid tumors. This research article describes the current status of clinical trials related to siRNA-based cancer therapy, as well as the remaining issues that need to be overcome to establish a successful therapy. It, then introduces various promising design strategies of delivery vehicles for stable and targeted siRNA delivery, including the prospects for future design. The current major strategies to design delivery vehicles for systemic siRNA delivery involve the construction of multimolecular assemblies from more than dozens of monomer components, including siRNA. The success of RNAi-based cancer therapy is closely associated with tumor biology as well as architecture of delivery vehicles. Tumor cell plasticity evokes a resistance mechanism against clinical treatments, and cancer stem cells are gradually being identified as the root of cancer recurrence. New target RNA genes should be discovered to increase apoptosis in cancer cells and simultaneously reduce side effects in normal and healthy cells. Multidisciplinary research studies will guide the development of highly effective and safer RNAi-based drugs in clinical trials.