Using drug-excipient interactions for siRNA delivery

Abstract

SiRNA is the trigger of RNA interference, a mechanism discovered in the late 1990s. To release the therapeutic potential of this versatile but large and fragile molecule, excipients are used which either interact by electrostatic interaction, passively encapsulate siRNA or are covalently attached to enable specific and safe delivery of the drug substance. Controlling the delicate balance between protective complexation and release of siRNA at the right point and time is done by understanding excipients-siRNA interactions. These can be lipids, polymers such as PEI, PLGA, Chitosans, Cyclodextrins, as well as aptamers and peptides. This review describes the mechanisms of interaction of the most commonly used siRNA delivery vehicles, and looks at the results of their clinical and preclinical studies.

Phospholipid-modified polyethylenimine-based nanopreparations for siRNA–mediated gene silencing: Implications for transfection and the role of lipid components

“…To overcome these barriers, the siRNA must be associated within a delivery system tailored specifically for high efficiency, and low immunogenicity and toxicity. Apart from virus-based carriers, polycations of a lipidic or polymeric nature have become popular siRNA carriers 4–6 .…”

Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells

“…To address these problems, two strategies have been pursued: development of noncharged and nonbiodegradable siRNA surrogates (10) and, more directly, development of delivery vehicles and strategies that would enable or enhance the entry of siRNA itself. Several siRNA delivery technologies have been reported thus far, including direct covalent conjugation of siRNA to lipids, peptides, or to aptamers; and noncovalent complexation of siRNA with polymers, biopolymers, nanotubes, lipid-based vehicles (e.g., lipopolyplexes, stable nucleic acid lipid nanoparticles), cyclodextrin polymer-based nanoparticles, fusion proteins, membrane translocation-modified magnetic nanoparticles, and antibodyprotamine conjugates (4,6,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).In 2000, we reported an extensive reverse engineering effort directed at the highly cationic HIV-Tat 9-mer peptide (RKKRRQRRR), showing that its ability to enter cells is related to its arginine content and, more specifically, to the number and array of its guanidinium groups (23). This finding led to the design of oligoarginine and guanidinium-rich peptoid cell penetrating agents and, subsequently, a wide range of designed nonpeptidic agents, more generally and accurately dubbed molecular transporters, differing in backbone structure but uniformly incorporating the key guanidinium head groups (24).…”

Development of a simple, biocompatible and cost-effective Inulin-Diethylenetriamine based siRNA delivery system

“…This is particularly true for the cationic polymers PEI that, although having high siRNA condensation and transfection ability, are not biodegradable and induce cellular death via necrosis and apoptosis in a variety of cells (Boeckle et al, 2004). To reduce the PEI induced cytotoxicity, a wide range of moieties were introduced to its structure (Oh and Park, 2009;Bruno, 2011) such as carboxyalkyl chains, PEG and other polymers/molecules. Whereas these modifications resulted in significantly reduced cytotoxicity, they induced a reduction in the neutralization capacity and siRNA condensation/stability.…”