Preparation of polyethylene glycol-polyacrylic acid block copolymer micelles with pH/hypoxic dual-responsive for tumor chemoradiotherapy.

Block copolymers of poly(ethylene glycol)-poly(acrylic acid) linked with metronidazole (MN-PAA-PEG) were prepared via carbodiimide and esterification methods, and self-assembled into core-shell micelles as nano radiosensitizers and carriers of doxorubicin (DOX) delivery. These DOX/MN-PAA-PEG micelles exhibited good pH value and hypoxia dual-responsive properties via analyzing the change of micelle size and drug‒release behavior under hypoxia humor condition. The results of the cell test indicated that DOX was efficiently delivered by DOX/MN-PAA-PEG micelles into the cell nuclei. Compared to 22.4 % of their DOX release under pH 7.4, the rate of DOX release from DOX/MN-PAA-PEG micelles under reducing condition (pH 5.0) was up to 55.9 %. DOX-loaded micelles under 600 MU electron radiation and hypoxia induced the rapidest apoptosis of the tumor-cells, indicating the synergistic effect of their radiotherapy and chemotherapy from the prepared micelles. In vivo investigation and fluorescence imaging revealed that MN-PAA-PEG possessed no toxicity on main organs, and DOX/MN-PAA-PEG micelles were mainly accumulated in the tumor site at 10 h of post-injection, suggesting their good passive tumor-targeted effect. These results suggested that DOX/MN-PAA-PEG micelles were promising candidates for chemoradiotherapy on tumor.