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 cellular 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 to achieve maximum gene knockdown. To explore this phenomenon further, aqueous RAFT (aRAFT) polymerization was utilized to synthesize hydrophilic-block-cationic copolymers in which the cationic block contains a statistical incorporation of a neutral, hydrophilic monomer such that the number of cationic groups remains unchanged but varies in distribution along the polymer backbone. These copolymers with varying charge density were then complexed with siRNA and siRNA analogues. Calorimetric and potentiometric investigations of these BICs revealed trends of increasing complex stabilities and polymer-oligonucleotide binding strengths with greater cationic block charge density. Finally, in vitro gene suppression studies revealed improved gene knockdown with increased charge density. Quantification of siRNA delivery and cell fractionation revealed higher cellular siRNA content as well as increased activation of the RNA interference pathway with greater charge density.

Variable charge density in siRNA-containing block ionomer complexes: Optimizing complex binding strength, stability, and gene suppression

255th National Meeting (2018)

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