Phosphatidylcholine-Polycaprolactone Linear–Dendritic Copolymers for Selective Intracellular Drug Delivery and Improved Antitumor Efficacy

Phosphatidylcholine and its derivatives are highly attractive for their ability to enhance both the circulation stability and the cellular uptake of drug carriers. However, the mechanism underlying the phospholipid surface function and the impact of phospholipid density on micelle performance remain poorly understood. Here, we report the synthesis of a series of novel linear-dendritic copolymers based on phosphatidylcholine-polycaprolactone, where varying amounts of phosphatidylcholine groups can be attached to a single junction point at one end of the polycaprolactone. These copolymers self-assemble in aqueous solution to form micelles with different morphologies, demonstrating improved stability, drug loading capacity, and release behaviors with an increasing phospholipid content. Importantly, the micelles exhibit selective cellular uptake with a significant phospholipid dose dependence and show excellent antitumor efficacy in vivo at low drug dosages. This work provides a facile approach to designing and preparing nonlinear phospholipid copolymers with branched topology, offering a promising platform for drug delivery applications.