Variable Charge Density in Block Ionomer Complexes for Enhanced siRNA Delivery

摘要

Block ionomer complexes (BICs) formed from electrostatic association between hydrophilic-block-cationic copolymers and small interfering RNA (siRNA) are known to serve as superior vehicles for gene delivery. Such BICs stabilize and protect the siRNA while conferring hydrophilicity and reduced cytotoxicity, and incorporation of a targeting moiety deters nonspecific cellular uptake. Our group has previously demonstrated that BIC stability and siRNA delivery efficacy strongly depend upon cationic block length: increased block length greatly stabilizes the complexes and also increases the time required for gene knockdown. To explore this phenomenon, aqueous reversible addition-fragmentation chain transfer (oRAFT) polymerization was utilized to synthesize hydrophilic-block-cationic copolymers in which the cationic block contains a statistical incorporation of neutral, hydrophilic monomer such that the number of cationic groups remains unchanged but varies in distribution along the polymer backbone. Complex characterization experiments and in vitro gene knockdown studies were then performed to analyze the effect of increased cationic spacing on drug efficacy.