Novel Chitosan Derivatives with Reversible Cationization and Hydrophobicization for Tumor Cytoplasm-Specific Burst Co-delivery of siRNA and Chemotherapeutics.

Despite the great potential of combination therapy based on siRNA and chemotherapeutics, an efficient vehicle with abilities of well drug co-loading, synchronizing in vivo trafficking, and target-specific co-burst release remains elusive, which results in a suboptimal synergistic potency. Herein, a novel chitosan amphiphile (PEI-ss-HECS-ss-OA, HSPO) with glutathione (GSH)-reversible cationization and hydrophobicization by polyethylenimine (PEI) and octylamine (OA), respectively, was developed for this purpose. HSPO spontaneously assembled in aqueous solution to be a micellar system and effectively co-encapsulated the two drugs with an adjustable dosage ratio. With a surface charge inversion strategy by hyaluronic acid (HA) coating, the HA(HSPO) co-delivery micelles with a negative surface charge (-21.45 ± 1.44 mV) and suitable size (192.52 ± 7.41 nm) selectively accumulated into CD44 overexpressed A549 tumors through a combination of passive and active targeting mechanism. Then, tumor cytoplasm-selective co-burst release was obtained through GSH triggered collapse of the amphiphilic assembly alongside a decrease of positive charge condensation, finally leading to an enhanced synergistic antitumor effect with a superior inhibition ratio of 86.63%. Overall, this study validated the great promise of HSPO as an efficient site-specific rapid co-trafficking vehicle of siRNA and chemotherapeutics for a remarkable synergistic tumor inhibition.