Minimizing systemic toxicity of doxorubicin via targeted delivery of hypoxia-sensitive polymersomes

Hypoxia is a hallmark of solid tumors that reduces chemotherapy efficacy and enhances systemic toxicity. This study evaluated hypoxia-sensitive polymersomes as a delivery system for doxorubicin (DOX) to improve antitumor efficacy and reduce side effects. Methods: Polymersomes were synthesized, loaded with DOX, and tested on cancer and healthy cells under normoxic and hypoxic conditions. Cytotoxicity, cellular uptake, apoptosis induction, and potential mechanism of degradation were assessed. In vivo efficacy was investigated in 4T1 tumor-bearing mice treated intravenously with free DOX or DOX-loaded hypoxia-sensitive polymersomes (three times 5 mg/kg). Tumor volume, body weight, histology, and immunochemistry were analyzed. In vitro, both free DOX and DOX-loaded polymersomes induced significant cytotoxicity and apoptosis. The effect was enhanced under hypoxia, consistent with elevated NQO1 expression. In vivo, both formulations suppressed tumor growth to a comparable degree; however, polymersome-treated mice exhibited markedly reduced weight loss, indicating lowered systemic toxicity. Histological examination showed extensive necrosis and architectural disruption in tumors from both treatment groups. Hypoxia-sensitive polymersomes effectively deliver doxorubicin to hypoxic regions, achieving tumor growth inhibition comparable to that of the free drug while reducing treatment-associated toxicity. These findings support encapsulated DOX as a promising strategy for safer chemotherapy in hypoxic cancers.