Design of Tumor Microenvironment-Responsive Drug–Drug Micelle for Cancer Radiochemotherapy

Concomitant radiochemotherapy is a major therapeutic strategy for treating malignant tumors. However, the greatest challenge is how to improve the therapeutic effect of radiochemotherapy to achieve the proper synergetic chemo-/radiotherapy for the tumor. In this study, ferrocenium (antitumor effect) and nitroimidazole (hypoxic cell radiosensitization) conjugates were synthesized to form amphiphilic ferrocenium-hexane-nitroimidazole (Fe-NI), which can self-assemble in aqueous solution. The Fe-NI micelles successfully encapsulate the hydrophobic chemotherapy drug doxorubicin (DOX) and are modified with hyaluronic acid (HA) by electrostatic interactions to form HA-Fe-NIs-DOX micelles. HA-Fe-NIs-DOX micelles rapidly release DOX under tumor hypoxia and a high glutathione (GSH) environment and achieve a synergetic chemo-/radiotherapy for the tumor based on the properties of nitroimidazoles and ferrocenes. The biodistribution results obtained in vivo reveal an effective accumulation in the tumor. The HA-Fe-NIs-DOX micelles show a significant radiosensitizing effect on the tumors, and the combination of chemotherapy and radiotherapy is realized for the treatment of tumor in vitro and in vivo. These findings illustrate that HA-Fe-NIs micelles are a promising candidate, which enhances the antitumor effects as a DOX delivery system, owing to the synergistic mechanisms of antitumor agents and chemo-/radiotherapy.