Environmentally responsive dual-targeting nanotheranostics for overcoming cancer multidrug resistance

[Display omitted] The development of multiple drug resistance (MDR) to chemotherapy and subsequent treatment failures are major obstacles in cancer therapy. An attractive option for combating MDR is inhibiting the expression of P-glycoprotein (P-gp) in tumor cells. Here, we report a novel chemosensitizing agent, XMD8-92, which can down-regulate P-gp. To enhance the specificity of MDR chemotherapy, a promising nanotheranostic micelle system based on poly(ethylene glycol)-blocked-poly(L-leucine) (PEG-b-Leu) was developed to simultaneously carry the anticancer drug doxorubicin, chemosensitizing agent XMD8-92, and superparamagnetic iron oxide nanoparticles (SPIOs). Featured with MDR environmentally responsive dual-targeting capability, controllable drug delivery, and efficient magnetic resonance (MR) imaging characteristics, the prepared nanotheranostics (DXS@NPs) showed outstanding in vitro cytotoxicity on MDR cells (SCG 7901/VCR) with only 53% of cells surviving compared to 90% of DOX-treated cells. Furthermore, efficient tumor inhibition and highly reduced systemic toxicity were exhibited by MDR tumor-bearing mice treated with DXS@NPs. Overall, the environmentally responsive dual-targeting nanotheranostics represent a promising approach for overcoming cancer MDR.