Poly(styrene-alt-maleic anhydride)-Based Diblock Copolymer Micelles Exhibit Versatile Hydrophobic Drug Loading, Drug-Dependent Release, and Internalization by Multidrug Resistant Ovarian Cancer Cells

摘要

Amphiphilic diblock copolymers of poly-(styrene-alt-maleic anhydride)- b-poly(styrene) (PSMA-b-PS) and poly(styrene-alt-maleic anhydride)-b-poly(butyl acrylate) (PSMA-b-PBA) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerizations. Polymers were well-controlled with respect to molecular weight evolution and polydispersity indices (PDI < 1.2). Additionally, RAPT allowed for control of diblock compositions (i.e., ratio of hydrophilic PSMA blocks to hydrophobic PS/PBA blocks) and overall molecular weight, which resulted in reproducible self-assembly of diblocks into micelle nanoparticles with diameters of 20—100 nm. Parthenolide (PTL), a hydrophobic anticancer drug, was loaded and released from the micelles. The highest loading and prolonged release of PTL was observed from predominantly hydrophobic PSMA-b-PS micelles (e.g., PSMA_(100)-b-PS_(258)), which exhibited the most ordered hydrophobic environment for more favorable core—drug interactions. PSMA_(100)-b-PS_(258) micelles were further loaded with doxorubicin (DOX), as well as two hydrophobic fluorescent probes, niile red and IR-780. While PTL released quantitatively within 24 h, DOX, IR-780, and nile red showed release over 1 week, suggesting stronger drug—core interactions and/or hindrance due to less favorable drug—solvent interactions. Finally, uptake and intracellular localization of PSMA_(100)-b-PS_(258) micelles by multidrug resistant (MDR) ovarian cancer cells was observed by transmission electron microscopy (TEM). Additionally, in vitro analyses showed DOX-loaded PSMA-b-PS micelles exhibited greater cytotoxicity to NCI/ADR RES cells than equivalent free DOX doses (75% reduction in cell viability by DOX-loaded micelles compared to 40% reduction in viability by free DOX at 10 μM DOX), likely due to avoidance of MDR mechanisms that limit free hydrophobic drug accumulation. The ability of micelles to achieve intracellular delivery via avoidance of MDR mechanisms, along with the versatility of chemical constituents and drug loading and release rates, offer many advantages for a variety of drug delivery applications.