NIR-II Photothermal Activation of TRPV1 Channels for Intracellular Magnesium Regulation by Porous Pd@Pt Core–Shell Nanostructure to Reverse Tumor Multidrug Resistance

Multidrug resistance (MDR) caused by overexpressed P-glycoprotein (P-gp) in cell membrane is the main barrier for clinical tumor chemotherapy. P-gp can pump the chemical drugs out of tumor cells depending on ATP-provided energy. Herein, a photothermal-driven intracellular magnesium ion (Mg 2+ ) regulation strategy is proposed to reverse drug resistance through constructing Mg 2+ - and doxorubicin (DOX, as model drug)-loaded bimetallic Pd@Pt nanostructure (DPd@PtM). Although DPd@PtM can deliver Mg 2+ into tumor cells through endocytosis, large amount of Mg 2+ releases outside cells. To this end, the photothermal effect of Pd@Pt nanostructure in the second near-infrared region is expected to activate the thermosensitive transient receptor potential cation channel subfamily V member 1 (TRPV1) channel for extracellular released Mg 2+ influx. Intercellular Mg 2+ accumulation suppresses tricarboxylic acid cycle to block intracellular adenosine triphosphate (ATP) production (cutoff energy supply for P-gp) and reduce O 2 consumption (downregulate P-gp expression), then inhibiting P-gp-mediated tumor MDR. Both in vitro and in vivo results demonstrate that DPd@PtM can open TRPV1 channel to elevate Mg 2+ level and then inhibit the P-gp activity to enhance intracellular DOX concentration for chemotherapy. It is believed that this photothermal-mediated tumor Mg 2+ regulation therapy based on reversing MDR is a promising strategy to kill cancer cells.