Optimization of Amphiphilic Miktoarm Star Copolymers for Anticancer Drug Delivery

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

Facile Fabrication of 10-Hydroxycamptothecin-Backboned Amphiphilic Polyprodrug with Precisely Tailored Drug Loading Content for Controlled Release

Polymeric prodrugs with precisely controlled drug loading content (DLC) and rapid intracellular destabilization generally require complicated chemistry that hinders large-scale manufacture. For this purpose, we reported in this study a facile construction of reduction-sensitive amphiphilic polyprodrugs with an anticancer drug, 10-hydroxycamptothecin (HCPT), and a hydrophilic poly­(ethylene oxide) (PEG) moiety as the alternating building blocks of the multiblock copolymer using Cu­(I)-catalyzed azide–alkyne cycloaddition (CuAAc) click coupling between azide-SS-HCPT-SS-azide and alkyne-PEG-alkyne. Adoption of PEGs with two different molecular weights (MWs) of 400 and 1450 Da (PEG400 and PEG1450) afforded two polyprodrugs with different DLCs. Both formulations can self-assemble into spherical micelles with hydrodynamic diameter smaller than 200 nm, and exhibit glutathione (GSH)-triggered degradation for promoted drug release. A further comparison study revealed that the PEG1450-based polyprodrug is a better formulation than the analogue constructed from PEG400 in terms of in vitro drug release behaviors, and cytotoxicity. This work thus provides a facile yet efficient strategy toward polymeric prodrugs with precisely controlled DLC and reduction-triggered degradation for enhanced anticancer drug delivery