Efficient Self-Immolative RAFT End Group Modification for Macromolecular Immunodrug Delivery

The reversible addition-fragmentation chain -transfer (RAFT) polymerization provides access to a broad variety of biocompatible and functional macromolecules for diverse polymer-drug conjugates. Due to thiocarbonylthio groups at the ends of each growing polymer chain, they can straightforwardly be converted into disufilde-containing self-immolative motives for reversible drug conjugation by traceless linkers. This may be relevant for RAFT-polymerized poly(N,N-dimethylacrylamide) (pDMA), which has been demonstrated to provide similar properties as poly(ethylene glycol) (PEG) in terms of improving the drug's poor pharmacokinetic profile or enhancing its bioavailability. For that purpose, we established a highly efficient one-pot reaction procedure for introducing various functionalities including both primary and secondary amines and primary alcohols and demonstrated their reversible conjugation and traceless release from pDMA's polymer chain end. Next, a first polymer-drug conjugate with a Toll-like receptor agonist exhibited significantly increased activity in vitro compared to conventional irreversibly covalently fixed variants. Finally, alpha-omega-bifunctional dye or drug conjugates could be generated by a cholesterol-modified RAFT chain-transfer agent. It facilitated the polymer-drug conjugate's internalization at the cellular level monitored by flow cytometry and confocal imaging. This approach provides the basis for a variety of potentially impactful polymer-drug conjugates by combining versatile small molecular drugs with a plethora of available RAFT polymers through reductive-responsive self-immolative linkers.

Automated summary

The reversible addition-fragmentation chain-transfer (RAFT) polymerization allows the synthesis of biocompatible and functional macromolecules for polymer-drug conjugates. By utilizing traceless linkers, the drug conjugates can be reversibly attached to and released from the polymer chain. This approach is particularly relevant for poly(N,N-dimethylacrylamide) (pDMA), which has shown similar properties to poly(ethylene glycol) (PEG) in improving drug pharmacokinetics and bioavailability. The incorporation of various functionalities in a one-pot reaction procedure has been demonstrated, along with reversible conjugation and traceless release. Moreover, the internalization of polymer-drug conjugates at the cellular level has been achieved using cholesterol-modified RAFT chain-transfer agents.