Redox-responsive hyaluronic acid nanogels for hyperthermia-assisted chemotherapy to overcome multidrug resistance

Although chemotherapy has been widely used in the treatment of many kinds of cancer, drug resistance and side effects are the main obstacles in the cancer chemotherapy that result in an inferior therapeutic outcome. For the design of drug delivery system, extracellular stability and intracellular effective release are also a pair of contradictions. In this research, gold nanorods (AuNRs) loaded hyaluronic acid (HA) nanogels with reduction sensitivity were prepared for the efficient intracellular delivery of doxorubicin (DOX). The aforementioned HACysNG@AuNR nanogels with cystamine (Cys) as crosslinker could remain stable in the physiological condition and release DOX rapidly in the mimic intracellular glutathione (GSH) condition. Meanwhile, the cellular uptake efficiency by the human breast carcinoma (MCF-7) cells was enhanced because of the highly expressed HA receptor (CD44) on the cytomembrane. However, further cell experiments verified that it was difficult to achieve desired results for drug-resistant human breast cancer (MCF-7 ADR) cells due to the reduced drug uptake and enhanced drug efflux. Interestingly, this multidrug resistance of MCF-7 ADR cells could be reversed after treated with near-infrared (NIR) light. This might ascribe to the hyperthermia generated by AuNRs under NIR, which suspended drug efflux process and led to excellent hyperthermia-assisted chemotherapy outcome. Overall, our studies suggested that AuNRs loaded reduction-sensitive HA nanogels were excellent candidates of drug carriers to reverse the drug-resistance and induce severe apoptosis of drug-resistant MCF-7 ADR cells.