Reversal of doxorubicin-resistance of MCF-7/Adr cells via multiple regulations by glucose oxidase loaded AuNRs@MnO2@SiO2 nanocarriers

Targeting to multiple MDR mechanisms is a desired strategy for efficient reversal of multidrug resistance (MDR). Herein, a multi-functional and hierarchical-structured AuNRs@MnO₂@SiO₂ (AMS) nanocarrier is reported for multiple regulations of MDR. The glucose oxidase (GOx) loaded AMS (AMS/G) showed efficient capabilities of hypoxia-relieving, O₂-generation enhanced cancer starvation therapy (CST), and near-infrared (NIR) laser photothermal therapy (PTT) to MCF-7/Adr, a doxorubicin (Dox)-resistant breast cancer cell line. It was revealed that hypoxia inducible factor-1α and heat shock protein 90, can be significantly down-regulated by AMS/G. The Dox resistance and the adenosine triphosphate (ATP)-binding cassette (ABC) transporters: P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP), can be dramatically reversed by the AMS/G+NIR treatment. Specifically, the hypoxia-relieving function can down-regulate all the three ABC transporters. The enhanced CST decreases the expression of MRP1. The PTT diminishes the BCRP and MRP1. Assisted by the multiple and synergistic reversal mechanisms, the Dox co-loaded AMS/G (AMS/D/G) with NIR laser significantly inhibited the cell proliferation, migration, and drug efflux at both normoxia and hypoxia conditions. Cell apoptosis is greatly induced in a caspase-3 dependent manner. Tumor ATP depletion and Dox accumulation were confirmed in vivo. The tumor growth inhibition is greatly and synergistically enhanced, without inducing obvious side effects. Collectively, the nanostructured AMS/D/G can inhibit multiple ABC transporters and provide a promisingly platform for highly efficient reversal of tumor drug resistance.