Optimization of Amphiphilic Miktoarm Star Copolymers for Anticancer Drug Delivery

Abstract

The preparation of various types of miktoarm star polymers with precisely controlled structures (A₂B, ABC, AB₂C₂, etc.) has made significant progress due to the considerable advances in the synthetic strategies, including multistep protections/deprotections, orthogonality, and integration of different polymerization techniques. However, compared to the well-developed synthesis methodologies, the investigations on miktoarm star copolymers as drug delivery vehicles remain relatively unexplored, especially for the relationship of their branched structures and properties as drug delivery systems. To elucidate this structure–property relationship of amphiphilic miktoarm star polymers, we prepared four different amphiphilic miktoarm star copolymers with the respectively identical molecular weights (MWs) of hydrophilic and hydrophobic moieties but different star structures using heteroinitiators that were synthesized by protection/deprotection strategies for integrated ring-opening polymerization of hydrophobic ε-caprolactone and atom transfer radical polymerization of hydrophilic oligo (ethylene glycol) monomethyl ether methacrylate (OEGMA). Further screening of an optimal formulation for anticancer drug delivery by the stability of micelles, in vitro drug loading capacity, drug release properties, cellular uptake efficacy, and cytotoxicity of doxorubicin (DOX)-loaded micelles showed that PCL₃POEGMA₁ micelles possessed the lowest critical micelle concentration, the highest drug loading content, and enhanced therapeutic efficiency for DOX release of all the synthesized four star copolymer constructs. This study thus provides preliminary guidelines and rationalities for the construction of amphiphilic miktoarm star polymers toward enhanced anticancer drug delivery