“Transforming enemy into friend” strategy-based stimuli responsive dual-drug liposomes for synergistic chemo-photodynamic therapy

Photodynamic therapy (PDT) induces aggravation of tumor hypoxia, which leads to worsening tumor invasiveness and metastasis. Combining hypoxia-responsive prodrugs with photosensitizers could transform "enemy" (tumor hypoxia) into "friend" (positive amplifier) to facilitate efficient activation of prodrugs. However, it remains challenging to develop a highly effective co-delivery nanoplatform due to the poor compatibility between vehicles and cargoes. Herein, we selected podophyllotoxin (PPT) as a model drug to synthesize hypoxia-responsive polyphenol prodrug (PAG). By introducing a chemical modification strategy, PAG and Chlorin e6 (Ce6) could be remotely co-encapsulated into liposomes (PAG/Ce6 LPs) at a synergistic ratio utilizing metal ions gradient. In vitro experiments demonstrated that PAG/Ce6 LPs could kill tumor cells through multiple pathways; i) generating reactive oxygen species (ROS) for direct cell killing; ii) consuming intracellular glutathione (GSH) to disturb intracellular redox homeostasis to induce tumor cell apoptosis. iii) aggravating hypoxia micro-environment to promote PPT release for chemotherapy. Furthermore, the excellent stability of PAG/Ce6 LPs guaranteed extended drug blood circulation time, enhanced tumor accumulation and improved anticancer efficacy. Additionally, PAG/Ce6 LPs kept fluorescence quench in circulation and specifically recovered at the tumor site, avoiding the obstacle of phototoxicity. Such a co-delivery nanoplatform, integrating hypoxia-responsive polyphenol prodrugs and photosensitizer into one nanocarrier, provides new insight into solving the challenges of chemo-photodynamic therapy.