Hypoxia-responsive block copolymer radiosensitizers as anticancer drug nanocarriers for enhanced chemoradiotherapy of bulky solid tumors

Abstract Radiosensitizers play an important role in the clinical radiotherapy of hypoxic solid tumors to improve therapeutic efficacy. However, the in vivo performance of clinically used small-molecule radiosensitizers is commonly compromised by low bioavailability in hypoxic tumor regions. Herein, amphiphilic block copolymer radiosensitizers are prepared from clinically approved poly(ethylene glycol)- block -poly( l -glutamic acid) (PEG- b -PLG) and metronidazole (MN) to obtain MN-grafted PEG- b -PLG (PEG- b -P(LG- g -MN)) via condensation reaction, which can self-assemble into core-shell micelles as nanoparticle-formulated radiosensitizers in aqueous solution. The radiosensitizers are demonstrated to possess significantly higher sensitization enhancement ratio (SER) of 2.18 and potent in vivo tumor ablation capability upon exposure to electron beam irradiation compared with clinically used sodium glycididazole (GS) with SER of 1.32. Moreover, after optimizing the ratios of carboxyl and MN groups, PEG- b -P(LG- g -MN) micelles can be used to encapsulate doxorubicin (DOX@HMs) efficiently. Hypoxia-responsive structural transformation of MN into hydrophilic aminoimidazole triggers fast DOX release from DOX@HMs. After intravenous injection of DOX@HMs, potent ablation capability against bulky solid tumors (∼500 mm 3 ) is realized at a low radiation dose (4 Gy) via enhanced chemoradiotherapy. Therefore, the developed novel amphiphilic block copolymer radiosensitizers can be concurrently used as high-efficiency radiosensitizers and hypoxia-responsive DOX nanocarriers for enhanced chemoradiotherapy.