DL-Menthol Loaded Polypyrrole Nanoparticles as a Controlled Diclofenac Delivery Platform for Sensitizing Cancer Cells to Photothermal Therapy

Cancer cells with up-regulated intracellular heat shock proteins (HSPs) expression under adverse heat environment during photothermal therapy (PTT) always resulted in inefficient oncotherapy. As the expression of HSPs is an energy-dependent manner, inhibiting the aerobic glycolysis pathway to realize tumor starvation and therefore consequently reducing the production of intratumoral adenosine 5'-triphosphate (ATP) would offer an efficient way for sensitizing cancer cells to PTT. DLM@PPy NPs, a polypyrrole (PPy)-based platform complexing with DL-menthol (DLM), was well-designed and successfully developed here as a near-infrared (NIR) light and thermo responsive drug delivery system. Benefiting from the volatile property of DLM and high photothermal conversion ability of PPy, the as-prepared DLM@PPy NPs could continuously generate bubbles under NIR light illumination, which is good for precisely controlling the release of encapsulated drug and monitoring the whole therapeutic process by ultrasound imaging. By encapsulating diclofenac (DC, an inhibitor of glucose transporter 1 to realizing tumor starvation) to form DC/DLM@PPy NPs, on-demand DC release could be easily achieved by selectively turning on/off the NIR light irradiation. After releasing DC in tumor lesion to reduce the generation of intratumoral ATP, a significant intensified cell-killing efficiency of PTT was observed. Thus, our study has demonstrated the good potential of DLM/PPy NPs as a stimuli-responsive DC delivery system for intensified PTT through inhibiting the aerobic glycolysis of cancer cells.