Time-performance relationship and the associated mechanism of tumor drug-efflux pump P-glycoprotein reversal induced by mild photothermal therapy.

Acquired multidrug resistance (MDR) has been the main cause leading to cancer therapy failure. Even though mild photothermal therapy (PTT) strategy has shown promise in overcoming tumor MDR, the detailed changing patterns of drug-resistant protein P-glycoprotein (P-gp) following photothermal treatment remains poorly understood. Herein, we utilized the iRGD-modified graphene oxide nanosheet (IPHG), a nanocarrier capable of tumor-targeted infiltration and photothermal conversion, to investigate the time-performance relationship and the associated mechanism of mild PTT-mediated P-gp regulation. For the first time we found that mild PTT could induce rapid reduction in P-gp levels within 3 h via ubiquitin-proteasome degradation. Doxorubicin (DOX)-loaded nanodrug (IPHG/DOX) was then fabricated to unveil the significance of P-gp reversal-synchronized drug release. The results exhibited that NIR-irradiated IPHG/DOX remarkably augmented intracellular DOX accumulation, increased DOX infiltration in tumor spheroids, and potentiated cytotoxicity against MCF-7/ADR cells. These novetherapys offer valuable insights into mild PTT-assisted MDR tumor therapies.