Arsenic Prodrug-Mediated Tumor Microenvironment Modulation Platform for Synergetic Glioblastoma Therapy.

Glioblastoma (GBM) has a distinct internal environment characterized by high levels of glutathione (GSH) and low oxygen partial pressure, which significantly restrict most drugs' effectiveness. Arsenic-based drugs are emerging candidates for treating solid tumors; however, relatively high doses in solo systems and inconsistent complementary systems severely damage the normal tissues. We proposed a novel covalently conjugated strategy for arsenic-based therapy via arsenic-boronic acid complex formation. The boronic acid was modified on silver (AgL) to capture As V under an alkaline condition named arsenate plasmonic complex (APC) with a distinct Raman response. The APC can precisely release the captured As V in lysosomal acidic pH that specifically targets TME to initiate a multimodal therapeutic effect such as GSH depletion and reactive oxygen species generation. In addition, GSH activation leads to subconverted As V into As III , which further facilitated glutathione peroxidase (GPx) and superoxide dismutase inhibition, whereas the tumor selective etching of the silver core triggered by endogenous H 2 O 2 that can oxidize to generate highly toxic Ag ions produces and supplies O 2 to help the alleviated hypoxia. Both in vitro and in vivo data verify the APC-based chemotherapy paving the way for efficient nanomedicine-enabled boronate affinity-based arsenic chemotherapeutics for on demand site-specific cancer combination treatment of GBM tumors.