Tumor Microenvironment Responds To Ferroptosis Combined With Photodynamic Therapy

At present,the incidence of cancer is still increasing year by year,and it has become the most important disease threatening human health and life in the world.Therefore,the effective treatment of tumor has become the focus of widespread concern.At present,the clinical therapeutic means mainly include surgery,radiotherapy and chemotherapy.However,in the actual treatment process,various treatment methods are still faced with various difficulties,such as the limitations of surgery for scattered tumor,linear tumor and large-scale metastasis,the risk of radiotherapy and the poor selectivity of chemotherapy,systemic toxicity and side effects.Therefore,exploring effective tumor treatment is still an urgent problem to be solved.However,there are complex relationships between tumor cells and surrounding cells and tissues,and tumor cells themselves have the characteristics of immune tolerance and immune escape.Therefore,there are always various limitations of single therapy,and multi-therapy fusion therapy has become a trend of treatment development.With the rapid development of polymer carrier,nanomedicine has become an important means of treatment.The rapid development of nanomedicine provides a new idea for the treatment of tumor.Compared with a single therapeutic method,nanomedicine can use the nano platform to integrate multiple therapeutic methods,make up for the deficiencies of single therapy,and inhibit tumor cells more efficiently.In addition,with high biosafety and biocompatibility,the nanosystem could selectively target tumor sites based on the enhanced permeability and retention effect（EPR）,providing conditions for selective treatment of tumors.Therefore,the development of multi-means synergistic treatment of nano drugs for tumor therapy has a good application prospect.In this study,Fe³⁺and epigallocatechin gallate（EGCG）were complexed to construct nanocarriers,and photosensitizer chlorin e6（Ce6）was loaded by self-assembly.Nano drug CFNPs was prepared for phototherapy and ferroptosis in combination with tumor treatment.microscope（TEM）and dynamic light scattering（DLS）results show that the particle size of CFNPs is about 130 nm.This provides security for targeting tumor sites through EPR effect.The metallic polyphenol network structure formed by EGCG and Fe³⁺can be disassembled by the stimulation of L-Glutathione（GSH）or p H,which provides the basis for the release of photosensitizer under the stimulation of tumor microenvironment after the arrival of nanodrugs at the tumor site and the implementation of photodynamic therapy.Furthermore,the ability of CFNPs to produce singlet oxygen（¹O₂）and hydroxyl radicals（·OH）in vitro demonstrates the potential of Photo Dynamic Therapy（PDT）as a synergistic treatment for ferroptosis.Fluorescence experiments on intracellular Reactive oxygen species（ROS）show that CFNPs can obviously produce ROS,and this phenomenon is effectively inhibited by the addition of ferroptosis inhibitors.Cytotoxicity results showed that CFNPs nanodrugs could effectively kill tumor cells,and the survival rate of cells could be effectively reversed by adding ferroptosis inhibitors,iron chelating agents,etc.,indicating that the system could play the synergistic effect of phototherapy and ferroptosis,which also provided help to alleviate the treatment limitations caused by hypoxia in single photodynamic therapy.Ferroptosis was then further verified.Deactivation of Recombinant Glutathione Peroxidase 4（GPX4）and the positive expression of Lipid hydroperoxide（LPO）in fluorescence imaging further indicates that CFNPs nanosystems perform the ferroptosis path well.More importantly,CFNPs nanomaterials can trigger Immunogenic cell death（ICD）,Recombinant Calreticulin（CRT）expulsion,the High expression of High Mobility Group Box 1（HMGB1）and the release of adenine nucleoside triphosphate（ATP）confirm this conclusion.In conclusion,on the basis of selectively targeting tumor cells using EPR effect,the nano-drug CFNPs constructed in this subject can combine photodynamic therapy and ferroptosis synergistic therapy and trigger ICD to effectively treat tumor,which provides a research basis for multi-means combined therapy and stimulation of immunotherapy.