Self-delivered and Self-monitored Chemo-Photodynamic Nanoparticles with Light-triggered Synergistic Anti-tumor Therapies by Downgrading HIF-1α and Depleting GSH.

Photodynamic therapy (PDT), a clinically approved cancer treatment, faced many drawbacks that restricted its applications. For example, the hypoxia-induced elevated hypoxia-inducible factor-1α (HIF-1α) may desensitize tumors to PDT, and the high concentration of GSH in cancer cells can also neutralize the generated ROS during PDT, resulting in insufficient therapy. Moreover, extra probes for imaging-guided visualization therapy are always needed to track the drug release or distribution while it may decrease the drug loading of the drug delivery system (DDS). In present study, we have designed and prepared a novel multi-functional combined therapy nanoparticle (ZnPc@Cur-S-OA NPs), in which Curcumin (Cur) was not only used as a chemotherapy drug to achieve a combination therapy with PDT via downregulating HIF-1α and depleting GSH in B16F10 cells but also designed as a small-molecule ROS-triggered release prodrug to deliver the photosensitizer (PS). The red fluorescence of PS in the nanoparticles (NPs) can be used to track the NPs distribution while the green fluorescence of Cur showed an "OFF-ON" activation, enables additional imaging and real-time self-monitoring capability. Results have proved that the prepared combined therapy NPs were more effective to inhibit the growth of B16F10 mouse melanoma tumor than monotherapy without eliciting systemic toxicity no matter in vitro or in vivo, which indicated the combined therapy NPs as an effective way to improve the PDT efficacy via downregulating HIF-1α and depleting GSH. Thus, the strategy of using a multi-functional natural product as the stimuli-responsive carrier as well as the synergist with PDT for enhancing anti-tumor efficacy via multiple pathways may open an alternative avenue to fabricate new self-delivery combination therapy nano-drugs. Besides, the fluorescence emitted from the drug can be used to real-time self-monitor the drug releasing and distributing, which has great potential in clinic to adjust the administration dose and irradiation time for different tumor types and stages for individual therapy.