Organocatalytic Anticancer Drug Loading of Degradable Polymeric Mixed Micelles via a Biomimetic Mechanism

Although self-assembled polymeric micelles have received significant attention as anticancer drug delivery systems, most of them suffer initial burst release of drugs after injection. Herein, a novel organocatalytic drug loading approach is reported to chemically conjugate anticancer drugs to the micellar core through an acid-labile bond that only breaks in the acidic tumor tissue and endolysosomal environments. Specifically, a degradable polymeric micelle system based on amphiphilic mPEG-b-polycarbonate block copolymers was developed. The mussel-inspired polymer design features catechol side chains to which the anticancer drug doxorubicin (DOX) can be covalently conjugated as pH-sensitive p-quinoneimines via a mechanism that mimics the Raper Mason pathway of mammalian melanogenesis. We demonstrate that a higher drug loading is achieved when N-methylimidazole is cointroduced during self-assembly as an organocatalyst. The DOX-loaded mixed micelles formed from a catechol-functionalized polycarbonate/PEG block copolymer and a sister polymer with imidazole side chains are kinetically stable and display no signs of premature drug release, but possess comparable cytotoxicity in cancer cells to free DOX by a pH-triggered intracellular release. Moreover, we show that the nanoparticles accumulate in tumors through the enhanced permeability and retention (EPR) effect, and that the DOX-loaded mixed micelles suppress tumor growth more effectively than free DOX without causing toxicity in a mouse breast cancer model.