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

Area of Science:

• Polymer chemistry
• Bioconjugation
• Antimicrobial drug delivery

Background:

• Polymer-antibiotic conjugates (PACs) offer advantages over free antibiotics, including modified solubility, sustained release, and prolonged bioactivity.
• Clindamycin (Clin) is a potent, broad-spectrum antibiotic with diverse medical uses, but Clin-containing PACs have not been previously reported due to modification challenges.
• Selective modification of clindamycin is difficult due to its multiple reactive hydroxyl groups.

Purpose of the Study:

• To develop an efficient and regioselective method for synthesizing methacrylic-functionalized clindamycin monomers.
• To synthesize well-defined water-insoluble and water-soluble clindamycin-containing PACs using reversible addition fragmentation chain transfer (RAFT) polymerization.
• To evaluate the structural characteristics, clindamycin content, sustained release behavior, and antibacterial activity of the synthesized PACs.

Main Methods:

• Utilized immobilized lipase as a biocatalyst for regioselective synthesis of a methacrylic-functionalized clindamycin monomer in a one-step reaction.
• Employed RAFT polymerization to create copolymers of the clindamycin monomer with 2-hydroxymethyl methacrylate (for water-insoluble PACs) or 3-[(3-acrylamidopropyl) dimethylammonio]propanoate (for water-soluble PACs).
• Characterized PAC structures and clindamycin content using 1H NMR and gel permeation chromatography; verified RAFT process living nature via chain-extension experiments; assessed antibacterial activity against Streptococcus mutans using zone of inhibition tests.

Main Results:

• Successfully synthesized methacrylic-functionalized clindamycin monomers using immobilized lipase.
• Produced well-defined water-insoluble and water-soluble clindamycin-containing PACs with high clindamycin content (33-46 wt%).
• Demonstrated sustained clindamycin release and significant antibacterial activity against Streptococcus mutans.

Conclusions:

• Presented an efficient method for synthesizing diverse clindamycin-containing PACs.
• The synthesized PACs exhibit sustained release and potent antibacterial properties.
• These novel PACs hold potential for various antibacterial applications.