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 activityin vitrocompared to conventional
irreversibly covalently fixed variants. Finally, α-ω-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.