Reductive Degradation Behavior of Bioreducible Poly(disulfide amine) for Enhancing SiRNA Efficiency

Abstract

Bioreducible cationic polymer poly(CBA-DAH) containing repeated disulfide linkages on the polymer backbone was synthesized through Michael-type polyadditions of CBA to DAH monomers. Poly(CBA-DAH) could spontaneously form nanoscale polyelectrolyte complexes through electrostatic interactions with siRNA in an aqueous phase. These nanoparticles were rapidly degraded under the reductive cytoplasmic environment with subsequently releasing the siRNA cargo into the cytoplasm where RNAi takes place, as a result of the breakdown of disulfide bonds in the polymers. The reductive degradation behavior of the poly(CBA-DAH)/siRNA polyplexes is more likely to increase RNAi activity with enhancing the cytoplasmic localization of siRNA molecules. Poly(CBA-DAH) may have great potential as a gene carrier especially for therapeutic applications of siRNAs owing to the reductive degradation characteristics.

EphA2 targeting peptide tethered bioreducible poly(cystamine bisacrylamide–diamino hexane) for the delivery of therapeutic pCMV-RAE-1γ to pancreatic islets

“…The inclusion of reducible disulfide bonds allows for the rapid triggered degradation upon entering the cytoplasmic compartment [34, 36]. The presence of primary and tertiary amines in the reducible polymer allow for the self-assembly of nucleic acid/polymer polyplexes [38].…”

Bioreducible polymers for therapeutic gene delivery

“…RNA interference (RNAi), which uses short 21–25 nucleotide RNAs (small-interfering RNAs, siRNAs) to recognize and degrade the target mRNA in a sequence-specific manner, has been considered as a potential therapeutic approach for the treatment of human genetic disorders caused by the over-expression of certain genes due to a strong gene silencing effect [114, 115]. Recently, different strategies of siRNA delivery by non-viral polymeric vehicles have been developed in vitro and in vivo [14].…”

“…Recently, different strategies of siRNA delivery by non-viral polymeric vehicles have been developed in vitro and in vivo [14]. The efficiency of RNAi mainly depends on the cytoplasmic localization of intact siRNAs, since RNAi only occurs in the cytoplasm where the target mRNA is translated [114, 116]. The VEGF siRNA/poly(CBA-DAH) polyplexes exhibited a relatively high efficiency of VEGF suppression (70.4% silencing) in a sequence specific manner without any cytotoxic effect detected, compared to VEGF siRNA/bPEI (49.7% silencing) (Fig.…”

“…The VEGF siRNA/poly(CBA-DAH) polyplexes exhibited a relatively high efficiency of VEGF suppression (70.4% silencing) in a sequence specific manner without any cytotoxic effect detected, compared to VEGF siRNA/bPEI (49.7% silencing) (Fig. 17(a)) [114]. …”

pH‐Sensitive Pentablock Copolymer Nanocapsules as Nontoxic and Efficient Gene Carriers

“…[10] Gene carriers with additional mechanisms that facilitate the dissociation of the complexes exhibit significantly enhanced transfection. [11,12] Nanogels, physically or chemically crosslinked hydrogel particles with a nanoscale size, have characteristics of both nanoparticles and hydrogels. [13] The unique properties of nanogels, such as high loading capacity for various bioactive agents, thermodynamic stability favorable to systemic circulation, rapid responsiveness to external stimuli such as pH and temperature, and enhanced cellular uptake, provide advantages for pharmaceutical nanocarriers.…”