Construction of a programmed activation nanosystem based on intracellular hypoxia in cisplatin-resistant tumor cells for reversing cisplatin resistance.

Cancer poses a significant threat to human life and health. Cancers treated with cisplatin invariably develop drug resistance. This challenge can be overcome by identifying and exploiting the vulnerabilities acquired by drug-resistant cancer cells, paving the way for finding effective novel treatment options for cisplatin-resistant cancers. Our previous study revealed that cisplatin resistance in cancer cells comes at the cost of increased intracellular hypoxia. In this study, we used 2-nitroimidazole modified hyaluronic acid (HA-NI) as the carrier. The cisplatin-resistant tumor cell specific intracellular hypoxia programmed activation nanomedicine (T/C@HN NPs) was constructed by the hypoxic toxic drug tirapazamine (TPZ) and encapsulating chlorin e6 (Ce6) into HA-NI using polymer assembly technology. The amphiphilic carrier could release free Ce6 molecules under the stimulation of intracellular hypoxic environment, and exhibit specific "activated state" photodynamic properties in cisplatin-resistant tumor cells. Upon irradiation, Ce6-mediated photodynamic therapy further intensifies hypoxia, amplifying its cytotoxicity. This project systematically evaluated the effects of T/C@HN NPs on the identification and recognition of cisplatin-resistant tumors using drug-resistant patient-derived xenograft (PDX) models. This study provides a promising avenue for the development of novel treatment of cisplatin-resistant tumors.