Intracellular glutathione-depleting polymeric micelles for cisplatin prodrug delivery to overcome cisplatin resistance of cancers

Abstract The intrinsic or acquired cisplatin resistance of cancer cells frequently limits the final therapeutic efficacy. Detoxification by the high level of intracellular glutathione (GSH) plays critical roles in the majority of cisplatin-resistant cancers. In this report, we designed an amphiphilic diblock copolymer composed of poly(ethylene glycol) (PEG) and polymerized phenylboronic ester-functionalized methacrylate (PBEMA), PEG- b -PBEMA, which can self-assemble into micelles in aqueous solutions to load hydrophobic cisplatin prodrug (Pt(IV)). Pt(IV)-loaded PEG- b -PBEMA micelles (PtBE-Micelle) reverse cisplatin-resistance of cancer cells through improving cellular uptake efficiency and reducing intracellular GSH level. We found that the cellular uptake amount of platinum from PtBE-Micelle was 6.1 times higher than that of free cisplatin in cisplatin-resistant human lung cancer cells (A549R). Meanwhile, GSH concentration of A549R cells was decreased to 32% upon treatment by PEG- b -PBEMA micelle at the phenyl borate-equivalent concentration of 100 μM. PtBE-Micelle displayed significantly higher cytotoxicity toward A549R cells with half maximal inhibitory concentration (IC 50 ) of cisplatin-equivalent 0.20 μM compared with free cisplatin of 33.15 μM and Pt(IV)-loaded PEG- b -poly( e -caprolactone) micelles of cisplatin-equivalent 0.75 μM. PtBE-Micelle can inhibit the growth of A549R xenograft tumors effectively. Accordingly, PEG- b -PBEMA micelles show great potentials as drug delivery nanocarriers for platinum-based chemotherapy toward cisplatin-resistant cancers.