A pH-sensitive micelle for codelivery of siRNA and doxorubicin to hepatoma cells

Aiming to effectively codeliver chemotherapeutic drugs (DOX) and siRNA (BCL-2 siRNA) into tumor cells, well-defined triblock copolymers composed of hydrophilic and hydrophobic blocks were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The poly(ethylene glycol) (PEG) macroRAFT agent and two pH-sensitive monomers (2-(diethylamino)ethyl methacrylate, DEA and 2-(dimethylamino)ethyl methacrylate, DMA) were used for synthesizing the copolymers consisting of pH-sensitive PDEA, PDMA and PEG blocks. At pH 10, the copolymer in aqueous solution self-assembled into a micelle with hydrophobic core consisting of PDEA and PDMA for doxorubicin (DOX) encapsulation, owing to the deprotonation of the side tertiary amino groups. At neutral pH, the hydrophobic core became porous and positively charged to allow siRNA complexation due to PDMA solubilization (the pK_a of PDMA is around 8.0). Inside the acidic lysosomal compartments, PDEA was protonated and thus became hydrophilic to result in rapid release of DOX. Moreover, existence of two pH-sensitive blocks PDMA and PDEA endowed the copolymer with proton buffering effect that facilitated lysosomal escape of nanocomplex and siRNA release inside cells. Our results showed that the two codelivered therapeutic agents acted synergistically on the human hepatic carcinoma HepG2 cells to induce apoptosis in a highly effective manner.