Dually enhanced phototherapy by gambogic acid and hyperthemia-activated chemotherapy for synergistic breast cancer treatment

Combining chemotherapy and phototherapy (including photodynamic therapy and photothermal therapy) via nanoscale drug delivery systems has been widely explored to improve the therapeutic efficacy of cancers. Nevertheless, deficient reactive oxygen species (ROS) level caused by the excessive antioxidants (e.g., glutathione (GSH)) in tumor cells and thermoresistance mediated by heat shock proteins (HSPs) represent two pivotal obstacles for phototherapy. In addition, limited control on drug release via conventional nanocarriers results in unpredictable side effects of chemotherapeutic drugs. To tackle these problems, a novel phase change material (PCM)-based nanoplatform co-delivering paclitaxel (PTX), IR780 and gambogic acid (GA) was developed via a facile method to achieve chemotherapy synergized by dually-enhanced phototherapy of breast cancers. PCM-based nanoparticles (NPs) revealed favorable particle size and greatly improved photostability of IR780. PCM endowed the NPs with hyperthemia-triggered release of PTX for chemotherapy, which was beneficial to dampen the side effects. Upon the cellular uptake, GA-depleted intracellular GSH and blocked the overexpression of HSP90, which in turn simultaneously increased the ROS level and suppressed thermoresistance to enhance the efficacies of PDT and PTT, respectively. Finally, the dually-energized phototherapy and PTT-activated low-dose PTX-based chemotherapy achieved outstanding antitumor performances in vitro and in vivo. Taken together, via the NIR-activatable PCM-based NPs, a strategy of harnessing a single enhancer to boost the efficacies of dual-modal phototherapy and low-dose chemotherapy has been established for improved cancer treatment and reduced side effects.