Synthesis of polymer-clindamycin conjugates through lipase-catalyzed esterification and RAFT polymerization

Abstract

Relative to free antibiotics, polymer-antibiotic conjugates (PACs) can possess modified solubility, sustained release behavior, and prolonged bioactivity in biological systems. As one of the most potent and ubiquitous antibiotics, clindamycin (Clin) has broad-spectrum antibiotic activity with versatile medical applications. However, polymer-Clin conjugates have not been reported yet. This can be partly ascribed to the difficulties in selective modification of Clin which possesses multiple reactive hydroxyl groups. In this study, we employed immobilized lipase as a bio-based catalyst for the facile and highly regioselective synthesis of a methacrylic-functionalized monomer-Clin conjugate via a one-step reaction. Reversible addition fragmentation chain transfer (RAFT) polymerization was then employed to synthesize copolymers of the monomer-Clin conjugate with 2-hydroxymethyl methacrylate or 3-[(3-acrylamidopropyl) dimethylammonio]propanoate to achieve water-insoluble and water-soluble Clin-containing PACs, respectively. These PACs possessed well-defined structures with high Clin content (33–46 wt%), as confirmed by ¹H NMR and gel permeation chromatography characterizations. Living nature of the RAFT process for the synthesis of PACs was verified by a chain-extension experiment. With sustained Clin release behavior, these PACs further demonstrated notable antibacterial activities against Streptococcus mutans, as verified by zone of inhibition tests. Collectively, this work presents an efficient method to synthesize different types of Clin-containing PACs, with potential for use in diverse antibacterial applications.