Therapeutic potential of chemically modified siRNA: Recent trends

Abstract

Small Interfering RNAs (siRNAs) are one of the valuable tools to investigate the functions of genes, and are also used for gene silencing. It has a wide scope in drug discovery through in vivo target validation. siRNA therapeutics are not optimal drug-like molecules due to poor bioavailability, immunogenic and off-target effects. In order to overcome the challenges associated with siRNA therapeutics, identification of appropriate chemical modifications that improves the stability, specificity and potency of siRNA is essential. This review focuses on the various chemical modifications and their implications in siRNA therapy.

Recent Advances in the Design of Self‐Delivery Amphiphilic Drugs and Vaccines

“…The exact mechanisms of how amphiphilic modification leads to subcellular organelle accumulation remain poorly established, but it is believed that the overall physicochemical properties and ligand–receptor interactions govern the intracellular sorting and trafficking pathways . For example, amphiphilic modification is an effective way for cytosolic targeting of small interfering RNAs (siRNA) . Lipophilic ligands modified siRNA associate with high density lipoproteins and cross the membrane directly into cytoplasm via non‐endocytotic pathway mediated by the scavenger receptor BI .…”

“…Lipophilic ligands modified siRNA associate with high density lipoproteins and cross the membrane directly into cytoplasm via non‐endocytotic pathway mediated by the scavenger receptor BI . A wide range of lipophilic moieties including cholesterol, fatty acids, and steroids were used for siRNA conjugation and some of them have reached clinical stage . Amphiphilic modification has also been utilized for the endosomal entrapment in drug delivery.…”

siRNAzos: A New Class of Azobenzene‐Containing siRNAs that Can Photochemically Regulate Gene Expression

“…Short interfering RNAs are a class of biological molecules that have the potential to be next generation therapeutics . However, due to issues related to delivery, stability, and off‐target effects, siRNAs still require some forms of chemical modification to make them effective pharmaceutical candidates …”

VEGF siRNA delivered by polycation liposome-encapsulated calcium phosphate nanoparticles for tumor angiogenesis inhibition in breast cancer

“…Free siRNA including VEGF siRNA and random siRNA showed little biological activity due to their instability and fast degradation. 29 In order to understand the potency of PLCP in tumor inhibition application, VEGF siRNA was delivered into the tumor xenografts. The results demonstrated that PLCP led to a significantly higher tumor growth inhibition than negative control saline (Figure 3), while the use of Scr siRNA showing little tumor inhibition also confirmed the sequence specificity in line with in vitro study.…”