RNAi Therapeutics: Current Status of Nanoncologic siRNA Delivery Systems (original) (raw)

siRNA Delivery Technology for Cancer Therapy: Promise and Challenges

ACTA MEDICA IRANICA, 2019

Small interfering RNAs (siRNA) technology has shown great promise as a new class of therapeutic interventions for the treatment of cancer and other diseases. It is a remarkable endogenous pathway that can regulate sequence-specific gene silencing. Despite the excitement about possible applications of this biological process for sequence-specific gene regulation, the major limitations against the use of siRNA-based therapeutics are their rapid degradation by serum nuclease, poor cellular uptake, and rapid renal clearance following systemic delivery, off-target effects and the induction of immune responses. Many researchers have tried to overcome these limitations by developing nuclease-resistant chemically-modified siRNAs and a variety of synthetic and natural biodegradable lipids and polymers to enhance the efficacy and safety profiles of siRNA delivery. Ideal siRNA-based delivery systems for cancer therapy must be clinically suitable, safe and effective. In this review, we introduce the greatest challenges in achieving efficient RNAi delivery and discuss design criteria and various delivery strategies for cancer therapy, including chemical modifications, lipid-based nanovectors, polymer-mediated delivery systems, conjugate delivery systems, and others.

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.

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.

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.

Insights on prospects of nano-siRNA based approaches in treatment of Cancer

Frontiers in Pharmacology , 2022

siRNA interference, commonly referred to as gene silence, is a biological mechanism that inhibits gene expression in disorders such as cancer. It may enhance the precision, efficacy, and stability of medicines, especially genetic therapies to some extent. However, obstacles such as the delivery of oligonucleotide drugs to inaccessible areas of the body and the prevalence of severe side effects must be overcome. To maximize their potential, it is thus essential to optimize their distribution to target locations and limit their toxicity to healthy cells. The action of siRNA may be harnessed to delete a similar segment of mRNA that encodes a protein that causes sickness. The absence of an efficient delivery mechanism that shields siRNA from nuclease degradation, delivers it to cancer cells and releases it into the cytoplasm of specific cancer cells without causing side effects is currently the greatest obstacle to the practical implementation of siRNA therapy. This article focuses on combinations of siRNA with chemotherapeutic drug delivery systems for the treatment of cancer and gives an overview of several nanocarrier formulations in both research and clinical applications.

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.

Small interfering RNAs (siRNAs) in cancer therapy: a nano-based approach

International Journal of Nanomedicine

Clinical Advances of siRNA-Based Nanotherapeutics for Cancer Treatment

Pharmaceutics, 2021

Cancer is associated with single or multiple gene defects. Recently, much research has focused on incorporating genetic materials as one of the means to treat various types of carcinomas. RNA interference (RNAi) conveys an alternative genetic approach for cancer patients, especially when conventional medications fail. RNAi involves the inhibition of expression of specific messenger RNA that signals for uncontrollable cell growth and proliferation, most notably with carcinoma cells. This molecular technology is promising as genetic materials allow us to overcome issues associated with chemotherapeutic agents including organ damage associated with severe drug toxicities. Nonetheless, vast challenges impede successful gene therapy application, including low tumor localization, low stability and rapid clearance from the blood circulation. Owing to the limited treatment opportunities for the management of cancer, the development of effective siRNA carrier systems involving nanotherapeuti...

Nanoparticle-mediated systemic delivery of siRNA for treatment of cancers and viral infections

Theranostics, 2014

RNA interference (RNAi) is an endogenous post-transcriptional gene regulatory mechanism, where non-coding, double-stranded RNA molecules interfere with the expression of certain genes in order to silence it. Since its discovery, this phenomenon has evolved as powerful technology to diagnose and treat diseases at cellular and molecular levels. With a lot of attention, short interfering RNA (siRNA) therapeutics has brought a great hope for treatment of various undruggable diseases, including genetic diseases, cancer, and resistant viral infections. However, the challenge of their systemic delivery and on how they are integrated to exhibit the desired properties and functions remains a key bottleneck for realizing its full potential. Nanoparticles are currently well known to exhibit a number of unique properties that could be strategically tailored into new advanced siRNA delivery systems. This review summarizes the various nanoparticulate systems developed so far in the literature for...

Nanomaterials-Based siRNA Delivery: Routes of Administration, Hurdles and Role of Nanocarriers

Nanotechnology in Modern Animal Biotechnology, 2019

Ribonucleic acid interference (RNAi) is a potential alternative therapeutic approach to knock down the overexpression of genes in several disorders especially cancers with underlying genetic dysfunctions. For silencing of specific genes involved in cell cycle, small/short interfering ribonucleic acids (siRNAs) are being used clinically. The siRNA-based RNAi is more efficient, specific and safe antisense technology than other RNAi approaches. The route of siRNA administration for siRNA therapy depends on the targeted site. However, certain hurdles like poor stability of siRNA, saturation, off-target effect, immunogenicity, anatomical barriers and non-targeted delivery restrict the successful siRNA therapy. Thus, advancement of an effective, secure, and long-term delivery system is prerequisite to the medical utilization of siRNA. Polycationic nanocarriers mediated targeted delivery system is an ideal system to remove these hurdles and to increase the blood retention time and rate of intracellular permeability. In this chapter, we will mainly discuss the different biocompatible, biodegradable, non-toxic (organic, inorganic and hybrid) nanocarriers that encapsulate and shield the siRNA from the different harsh environment and provides the increased systemic siRNA delivery.

RNAi Therapeutics: Current Status of Nanoncologic siRNA Delivery Systems (original) (raw)

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