Z-Group ketone chain transfer agents for RAFT polymer nanoparticle modification via hydrazone conjugation

Macromolecules. 2012 Sep 11;45(17):6766-6773. doi: 10.1021/ma301536f. Epub 2012 Aug 30.

Abstract

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 co-polymers. Post-polymerization ketal cleavage revealed ketone functionality at the polar terminus of an amphiphilic block co-polymer. Hydrazone-formation was facile in both organic solution as well as in 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°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.