A Multimodal Therapeutic Nanoplatform Overcoming Tumor Hypoxia Heterogeneity for Improved Tumor Chemoradiotherapy

The hypoxic nature of solid tumors limits the efficacy of radiotherapy (RT) and leads to radiation resistance. Hypoxic radiosensitizers can enhance tumor radiosensitivity by mimicking the effects of oxygen, but their efficacy has been limited by the heterogeneous oxygen distribution in tumor tissue. Herein, a multimodal therapeutic nanoplatform fabricated by co-encapsulation of chlorin e6 and tirapazamine (TPZ) with an amphiphilic polymeric conjugate of cisplatin (CDDP) and metronidazole is reported. This platform could kill the tumor periphery cells by the deeply penetrated oxygen-consuming sonodynamic therapy and unify the heterogeneously hypoxic context simultaneously, which then actuate the release and activation of the loaded TPZ. TPZ could further sensitize RT along with CDDP and metronidazole residues under the resultant hypoxic condition, which significantly decreases the radiation dosage required to cause massive cell damage. Except for the significantly suppressed tumor growth and metastasis caused by the multimodal therapeutic nanoplatform, its hypoxia-directed feature also endows it with excellent safety.