Development of pH–responsive nanocarriers using trimethylchitosans and methacrylic acid copolymer for siRNA delivery

Chitosan and its derivatives as nanocarriers for siRNA delivery

“…Nevertheless, transfectivity was significantly different from that of native chitosan, which is likely due to the higher positive charge of TMC that led to enhanced cellular uptake compared to that of chitosan/siRNA complexes [27]. No noteworthy effect for the degree of chitosan quaternization was noticed on the silencing activity, which is consistent with other works [18]. On the other hand, chitosan trimethylation slightly reduced chitosan viability which contradicts other findings in different cell lines [91].…”

“…For lysosomal escape of siRNA, membrane destabilizing agents have been used to promote its release into the cytosol in a sufficient quantity, such as fusogenic peptides [47] and lipids [48], as well as pH-responsive lipids [49] or polymers [18] and reduction-sensitive polymers [50,51]. The pH-responsive polymers, containing protonable amines, such as the cationic ones, are hypothesized to have a proton sponge effect or buffering capacity whereby proton influx is initiated through a vesicular ATPase-driven pump.…”

“…The pH-responsive polymers, containing protonable amines, such as the cationic ones, are hypothesized to have a proton sponge effect or buffering capacity whereby proton influx is initiated through a vesicular ATPase-driven pump. Then, electrostatic repulsion occurs between the protonated amine groups leading to complex swelling or expansion, which results in raising internal osmotic pressure and counter-ion penetration to end up with endosomal membrane rupture and, subsequently, siRNA release [13,18]. Endosomal escape might also be mediated by reduction, generated through a disulfide bond [2].…”

“…Thereby, different strategies have been adopted, such as the use of pH sensitive polyelectrolytes (cationic or anionic) that possess a high proton "sponge effect" [18,108], as well as the inclusion of other compounds possessing an endosomolytic effect [65,90] and the conjugation to some functional groups or polymers [78,91]. For instance, to introduce secondary and tertiary amines into chitosan in order to ameliorate its buffering capacity and solubility at high pH, Mittnacht et al conjugated imidazole to chitosan (Mw = 140 kDa) to deliver siRNA [82].…”

“…The incorporation of this polyelectrolyte improved transfection efficacy of TMC/siRNA complexes, which could be ascribed to the proton sponge mechanism combined with the endosomal membrane rupture. This may occur as a consequence of complex swelling and/or Eudragit conformational change, mediated by the protonation of its carboxylic group, under the acidic conditions found in the endosome [18].…”