Immunodrug Delivery by Self-Accelerating Degradable Polycarbonate Micelles with Transiently Stable Hemiacetal Ester Side Chains

Abstract

Despite the abundance of established micellar materials for (immuno)drug delivery, they often lack degradability, which is considered a significant aspect toward clinical translation. In this study, we introduce amphiphilic polycarbonates with transiently stable hemiacetal ester side chains, providing a promising degradable alternative to traditional ester side chains but with unique degradation profiles. Cyclic aliphatic carbonate monomers with hemiacetal ester groups can undergo ring-opening polymerization under base catalysis initiated by pyrene butanol or mPEG_5k–OH. In water, the resulting block copolymers efficiently self-assemble into polymeric micelles. Initial evidence from NMR and dynamic light scattering (DLS) studies suggests that the hemiacetal ester groups are likely to degrade upon exposure to aqueous solutions, however, remaining significantly stable within the micellar core. We hypothesize that this “on–off” degradation behavior is advantageous, as it reduces potential off-target interactions of liberated amphiphilic molecules with biological species. Additionally, the gained hydrophilicity resulting from side-chain degradation facilitates the breakdown of the polycarbonate backbone compared with aliphatic polycarbonates with hydrophobic ester side groups. Moreover, the polymer end groups can be converted to pentafluorophenyl carbonates for covalent dye labeling. Flow cytometry and microscopy experiments confirm micellar cell uptake and the successful codelivery of covalently attached and hydrophobically encapsulated dyes. Additionally, the micelles effectively solubilize the immunostimulatory drug CL075, mitigating its concentration-dependent toxicity. Our results suggest that self-accelerating degradable polycarbonate micelles derived from transiently stable hemiacetal ester side chains can be applied as a valuable nanosized immunodrug delivery platform.