Self-Immolative RAFT-Polymer End Group Modification

Abstract

Reversible modifications of reversible addition–fragmentation chain transfer (RAFT)-polymerization derived end groups are usually limited to reductive degradable disulfide conjugates. However, self-immolative linkers can promote ligation and traceless release of primary and secondary amines as well as alcohols via carbonates or carbamates in β-position to disulfides. In this study, these two strategies are combined and the concept of self-immolative RAFT-polymer end group modifications is introduced: As model compounds, benzylamine, dibenzylamine, and benzyl alcohol are first attached as carbamates or carbonates to a symmetrical disulfide, and in a straightforward one-pot reaction these groups are reversibly attached to aminolyzed trithiocarbonate end groups of RAFT-polymerized poly(N,N-dimethylacrylamide). Quantitative end group modification is confirmed by 1H NMR spectroscopy, size exclusion chromatography, and mass spectrometry, while reversible release of attached compounds under physiological reductive conditions is successfully monitored by diffusion ordered NMR spectroscopy and thin layer chromatography. Additionally, this concept is further expanded to protein-reactive, self-immolative carbonate species that enable reversible bioconjugation of lysozyme and α-macrophage mannose receptor (MMR) nanobodies as model proteins. Altogether, self-immolative RAFT end group modifications can form the new basis for reversible introduction of various functionalities to polymer chain ends including protein bioconjugates and, thus, opening novel opportunities for stimuli-responsive polymer hybrids.