Tumor-specific carrier-free nanodrugs with GSH depletion and enhanced ROS generation for endogenous synergistic anti-tumor by a chemotherapy-photodynamic therapy

A novel carrier-free GA-Ce6-FA NPs with the GSH depletion was developed to achieve a remarkable chemotherapy-PDT synergistic anti-tumor effect. [Display omitted] •The self-assembly GA-Ce6-FA NPs was designed for chemotherapy combined with PDT.•GA-Ce6-FA NPs was a pH-triggered drug release system with tumor targeting by FA.•Depleting GSH by GA-Ce6-FA NPs was an effective way to improve PDT efficacy.•GA-Ce6-FA NPs hold a good anti-tumor effect with a potential for tumor imaging. Combining chemotherapy and photodynamic therapy (PDT) with a nanoscale drug delivery system (NDDS) has been widely developed to improve the therapeutic efficacy and biological safety of current treatments. However, the excess glutathione (GSH) in tumor cells impedes the ROS generation from photosensitizers, leading to reduction of PDT efficacy. Moreover, most NDDS also have been restricted due to the complexity of the multi-component, batch to batch differences, carrier-related toxicity and poor drug loading issues. To overcome these problems, a novel carrier-free nanodrug (GA-Ce6-FA NPs) was developed to achieve chemotherapy combined PDT synergistic treatment by a simple and green self-assembly approach, and the NPs was made up of gambogic acid (GA), chlorin e6 (Ce6) and folic acid (FA), in which GA was not only used as a chemotherapy drug but also designed to deplete GSH in tumor for enhancing PDT efficacy. The GA-Ce6-FA NPs exhibited a diameter of ~135 nm, which favored the NPs accumulation in tumor by a potential EPR effect. Meanwhile, the GA-Ce6-FA NPs had a pH-triggered drug release profile under a weak acidic condition, which could fast release drugs at the tumor region. It significantly enhanced the intracellular Ce6 uptake due to FA active targeting. Moreover, GA-Ce6-FA NPs could induce efficient apoptosis of MCF-7 cells, and offer a significant anti-tumor function by chemotherapy-PDT, which indicated depleting GSH by chemotherapeutics was an effective way to improve the efficacy of PDT. Thus, by the carrier-free NPs, a strategy of using multi-functional anticancer drugs as endogenous synergistic agents to PDT is useful to enhance anti-tumor efficacy.