Hypoxia-Responsive Nanomicelle Based on 2-Nitroimidazole for Tumor Treatment Through Chemotherapy and Modulation of the Tumor Redox Microenvironment

Hypoxia has evolved from being considered a mere byproduct of the tumor microenvironment to a recognized active contributor to tumor development, invasion, and metastasis, highlighting the importance of targeting hypoxia as a therapeutic strategy to improve oncological outcomes. In this study, we developed a straightforward drug delivery system that responds to hypoxic conditions using the organic solvent volatilization technique. We synthesized an amphiphilic polymer, poly(ethylene glycol)-phthalic acid-nitroimidazole (PEG-PA-NI), by linking hydrophilic poly(ethylene glycol) (PEG) to nitroimidazole acyl through an amidation reaction. This polymer was then used to create hypoxia-responsive nanoscale micelles (HRM NPs), which were loaded with the chemotherapeutic drug doxorubicin (DOX), and the resulting construct was termed hypoxia-responsive nanoplatforms (HRM@DOX NPs). Within the hypoxic and reducing tumor microenvironment, the hydrophobic compound 2-nitroimidazole undergoes conversion into its hydrophilic counterpart, 2-aminoimidazole, which is catalyzed by the overexpressed nitroreductase enzyme, leading to the disruption of the micelle structure and the accelerated release of the drug. This enzymatic transformation relies on the cofactor-reduced nicotinamide adenine dinucleotide phosphate (NADPH). Importantly, this conversion also disrupts the redox balance within the cancer cells, facilitating tumor cell apoptosis. Through experiments measuring changes in oxidized nicotinamide adenine dinucleotide phosphate hydrogen (NADP(+)) and glutathione (GSH) content in tumor tissues of mice, we demonstrated that HRM NPs could disrupt the redox balance within tumor cells under hypoxic conditions and enhance the therapeutic effects of chemotherapeutic drugs. This innovative hypoxia-responsive nanoplatform not only enhances drug release under hypoxic conditions but also induces a disruption in the redox balance specific to cancer cells, thereby promoting apoptosis. The utilization of hypoxia-sensitive polymers presents a promising avenue for advancing the effectiveness of cancer treatments, ensuring targeted therapeutic responses with minimized impact on healthy tissues.