NO-releasing polypeptide nanocomposites reverse cancer multidrug resistance via triple therapies.

ABSTRACT Multidrug resistance (MDR) induced by the overexpression of P-glycoprotein (P-gp) transporters mainly leads to chemotherapy (CT) failure. Herein, a NIR/pH dual-sensitive charge-reversal polypeptide nanocomposite (PDA-PLC) was developed for co-delivering a nitric oxide (NO) donor and doxorubicin (DOX). Under near-infrared (NIR) irradiation, the released high-concentration of NO gas inhibited the P-gp expression to sensitize the chemotherapeutic medicine DOX and assisted photothermal therapy (PTT) to eradicate cancer cells without skin scarring. Further, the distinctive charge-reversal capacity of PDA-PLC significantly facilitated cellular uptake in the tumor acidic microenvironment (pH 6.8) and enhanced its stability in the physiological environment (pH 7.4). This DOX-loading polypeptide nanocomposite (PDA-PLC/DOX) provides an effective strategy for the PTT-NO-CT triple-combination therapy to overcome MDR Statement of significance Multidrug resistance (MDR) has been considered to be the paramount factor of chemotherapy (CT) failure in cancer. In this work, an NIR/pH dual-sensitive charge-reversal polypeptide nanomedicine (PDA-PLC/DOX) was developed to overcome MDR through the triple combination therapy of photothermal therapy (PTT), NO gas therapy, and CT. The distinctive charge-reversal capacity of PDA-PLC/DOX significantly facilitated cellular uptake in the tumor acidic microenvironment (pH 6.8) and enhanced its stability in the physiological environment (pH 7.4), while the NIR trigger-released NO gas greatly inhibited the expression of P-gp and synergistically enhanced PTT and CT efficacy. This polypeptide nanocomposite PDA-PLC/DOX provides an effective strategy of using the PTT-NO-CT triple combination therapy with charge-reversal property to completely eradicate the MCF-7/ADR tumor.