Design of pH-Degradable Polymer-Lipid Amphiphiles Using a Ketal-Functionalized RAFT Chain Transfer Agent

Conjugation of small molecule drug to lipid-polymer amphiphiles is a powerful strategy to alter the pharmacokinetic profile of these molecules by promoting binding to albumin or other serum molecules. Incorporation of a responsive linker between the lipid anchor and the polymer chain can be of interest to avoid indefinite binding of the conjugates to hydrophobic pockets of serum proteins or phospholipid membranes when reaching a target cell or tissue. Here, the synthesis of pH-sensitive lipid-polymer conjugates by reversible addition-fragmentation chain transfer (RAFT) polymerization using a RAFT chain transfer agent that is equipped with a pH-sensitive ketal bond between a cholesterol moiety and the trithiocarbonate RAFT chain transfer group is reported. It is demonstrated that in native form these conjugates exhibit a high affinity to albumin and cell membranes but loose this ability in response to a mild acidic trigger in aqueous medium.