pH/redox sequentially responsive nanoparticles with size shrinkage properties achieve deep tumor penetration and reversal of multidrug resistance.

Multidrug resistance (MDR) remains a serious impediment to successful tumor chemotherapy. Despite considerable efforts to address MDR, limited approaches have been successful in the clinic to date. Here, we have developed pH/redox cascade-sensitive multiscale nanoparticles (DMA-NPs) with size- and charge-changeable properties for the efficient delivery of a non-P-glycoprotein substrate anticancer drug (podophyllotoxin, PPT) to combat MDR. DMA-NPs are composed of a charge-reversible polymer (PEG-PAH-DMA) shell and a redox-sensitive small-sized dendrimeric PPT-prodrug (PAMAM-ss-PPT) core. The PEG-PAH-DMA polymer shell on DMA-NPs maintains a negative charge in a normal environment, which reverts to a positive charge in a mildly acidic tumor environment (pH 6.5), leading to the release of positive PAMAM-ss-PPT via electrostatic repulsion. PAMAM-ss-PPT completely releases PPT under elevated intracellular glutathione (GSH) conditions in tumors. Several properties facilitate the hierarchical transport of DMA-NPs across multiple drug resistance pathological obstacles, including long blood circulation times, significant accumulation in tumors, deep tumor permeation, cancer cell internalization, and rapid and complete drug release. Experimental evaluations, both in vitro and in vivo, collectively indicate that nanomedicines can effectively penetrate xenografted A549 paclitaxel-resistant lung cancer cells and inhibit tumor proliferation with negligible toxicity. The current study presents a novel nanoparticle-based therapeutic strategy aimed at overcoming MDR.