Z-Group Ketone Chain Transfer Agents for RAFT Polymer Nanoparticle Modification via Hydrazone Conjugation

A ketal-containing trithiocarbonyl compound has been synthesized and characterized as a chain transfer agent (CTA) in reversible addition fragmentation transfer (RAFT) polymerization. The ketal functionality does not interfere with RAFT polymerization of acrylate monomers, which proceeds as previously reported to yield macro-CTA polymers and block copolymers. Postpolymerization ketal cleavage revealed ketone functionality at the polar terminus of an amphiphilic block copolymer. Hydrazone formation was facile in both organic solution and aqueous buffer where polymer nanoparticle assemblies were formed, indicating a conjugation/end-functionalization yield of 40-50%. Conjugation was verified with fluorescein, biotin, and Gd-DOTA derivatives, and though the trithiocarbonate linkage is hydrolytically labile, we observed stable conjugation for several days at pH 7.4. and 37 degrees C. As expected, streptavidin binding to biotinylated polymer micelles was observed, and size-change-based relaxivity increases were observed when Gd-DOTA hydrazide was conjugated to polymer micelles. Cell uptake of fluorescently labeled polymer micelles was also readily tracked by FACS and fluorescence microscopy. These polymer derivatives demonstrate a range of potential theranostic/biotechnological applications for this conveniently accessible keto-CTA, which include ligand-based nanoparticle targeting and fluorescent/MR nanoparticle contrast agents.