Reversing multidrug resistance (MDR) remains a big challenge in cancer therapy. Combining the hyperthermia and chemotherapy is a promising strategy for efficient cancer treatment with MDR reversal. Gold nanocages (GNCs) are an ideal photothermal (PTT)-chemotherapy integration platform due to their good photothermal conversion efficiency and the unique hollow interiors. However, insufficient tumor cell internalization and in vivo premature drug leakage restrict the anticancer activity of GNCs-based drug delivery systems. Methods: pH low insertion peptide (pHLIP)- and thermoresponsive poly(di(ethylene glycol) methyl ether methacrylate-co-oligo(ethylene glycol) methyl ether methacrylate) polymer-conjugated GNCs were rationally constructed to load anticancer drug doxorubicin (DOX@pPGNCs). Tumor acidic environment-responsive tumor cell internalization, and near-infrared (NIR) laser-induced tumor accumulation, penetration and on-demand drug release were systematically examined. Results: DOX@pPGNCs display good photothermal efficacy and thermoresponsive property. NIR laser irradiations at the tumor site significantly enhance tumor accumulation and penetration. Once DOX@pPGNCs reach the tumor site, the conformational transformation of pHLIP at the acidic tumor microenvironment contributes to the enhanced cellular internalization. Furthermore, NIR laser-triggered photothermal effects induce the shrinkage of thermoresponsive polymer, resulting in the opening of the pores of GNCs and a rapid intracellular DOX release to the nuclei. DOX@pPGNCs exhibit synergistic antitumor effect with MDR reversal in vitro and in vivo. Conclusion: DOX@pPGNCs present strong potential to overcome MDR in cancer.
Keywords: multidrug resistance reversal; on-demand drug release; pHLIP; temperature-sensitive polymer; tumor accumulation and penetration; tumor cell targeting.