Nir/Ph Dual-Sensitive Polypeptide Nanocomposite Charge-Reverse, Generates No for Triple-Combination Therapy to Reverse Cancer Multidrug Resistance

Abstract

The multidrug resistance (MDR) induced by the overexpression of P-glycoprotein (P-gp) transporters mainly leads to the chemotherapy (CT) failure. Herein, a novel NIR/pH dual-sensitive charge-reversal polypeptide nanocomposite (PDA-PLC) was developed for co-delivering nitric oxide (NO) donor and doxorubicin (DOX). Under intelligent near-infrared (NIR) irradiation, the released high-concentration NO could inhibit the P-gp expression to reverse MDR, and assist photothermal therapy (PTT) to eradicate cancer cells without skin scarring. Meanwhile, the distinctive charge-reversal capacity of PDA-PLC significantly facilitates the cellular uptake at tumor acid microenvironment (pH 6.8) and enhances its stability at physiological environment (pH 7.4). This DOX-loading polypeptide nanocomposites PDA-PLC/DOX provide an effective strategy for the PTT-NO-CT triple-combination therapy to overcome MDR.