siRNA-based Nanoparticles for Cancer Therapy: Hurdles and Hopes

Abstract

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.

<p>Small interfering RNAs (siRNAs) in cancer therapy: a nano-based approach</p>

“…The specificity of action carried out by siRNA molecules depends upon the uniqueness of the selected sequences; however, many other factors may also have an impact on a lack of specificity 70. Several types involving siRNA off-target effects have been described and thoroughly reviewed 71.…”

Progress in Natural Compounds/siRNA Co-delivery Employing Nanovehicles for Cancer Therapy

“…Although siRNAs are important in anticancer therapy, there are a number of extracellular and intracellular barriers that challenge their efficacy . Among these siRNA limitations, off-targeting, their instability in blood circulation, inadvertent stimulation of the host’s immune responses, as well as their incapability to enter cells (cell uptake) are the most important . With respect to off-targeting, it has been reported that one-tenth of siRNAs affect unintended genes .…”

“…71 Among these siRNA limitations, offtargeting, their instability in blood circulation, inadvertent stimulation of the host's immune responses, as well as their incapability to enter cells (cell uptake) are the most important. 95 With respect to off-targeting, it has been reported that one-tenth of siRNAs affect unintended genes. 78 In addition, siRNAs triggers immunotoxicity by inducing inflammation and enhancing the levels of cytokines.…”

Bioengineered siRNA-Based Nanoplatforms Targeting Molecular Signaling Pathways for the Treatment of Triple Negative Breast Cancer: Preclinical and Clinical Advancements

“…The fate of successfully internalized siRNA were also greatly influenced by cell surface recycling, lysosomal degradation by lysozyme within cytosol and intracellular compartments release. All these criteria mentioned cause systemic delivery of siRNAs deemed challenging [ 28 , 29 , 30 ]. A growing number of studies have been implicated to develop safe and effective siRNA-targeted delivery systems with the means of utilizing viral and non-viral vehicles [ 31 , 32 ].…”