Metal-organic Framework-based Nanomaterials For Remodeling Hypoxic Microenvironment And Enhanced Photodynamic Therapy Of Pancreatic Cancer

Objective: In recent years,photodynamic therapy for pancreatic cancer has attracted widespread attention.However,due to the physiological characteristics of pancreatic cancer cells,the characteristics of highly dense stroma and the microenvironment of hypoxic tumors,the therapeutic effect of tumors is often not ideal.How to make photodynamic therapy play a greater role is also a hot spot of current general research.Therefore,this project designed a metal organic framework material that can carry the photosensitizer Ce6 and can improve the hypoxic state of the tumor microenvironment and enhance the killing effect of photodynamic therapy on pancreatic cancer.Maybe this will be a lot of clinical and scientific researchers in the Sensitization photodynamic therapy provides new theoretical support.Methods: The metal-organic framework material MOFs（MIL-100（Fe））was synthesized,and nanoparticle composites were formed by carrying Ce6 as a photosensitizer.F127（F127）Surface modification and characterization of nanomaterials.MTT method was used to detect the killing of cells by nanoparticles,inverted fluorescence microscope was used to detect ROS generation of each group after laser processing.Animal level experiments are divided into five groups: PBS,Ce6@F127-MOFs/Light,Free Ce6/Light,F127-MOFs/Light,Ce6@F127-MOFs/Light,monitor the tumor growth curve,and verify the effect of photodynamic therapy.Organ HE staining further verified the biosafety of nanomaterials and tumor TUNEL staining,and Ki67 staining was used to detect tumor cell apoptosis and proliferation.Results: The MIL-100（Fe）NPs nanoparticles with an average size of 220.2nm were successfully prepared,and the distribution range was 122-458 nm.The average DLS size of the F127-modified MIL-100（Fe）NPs was about 164.2nm,and the distribution range was 91-295 nm.In 10% serum,the particle size of MIL-100（Fe）NPs gradually increased over time（226.7nm-304.7nm）,while the particle size of nanoparticles modified by F127 tended to be stable（167.4nm-169.4 nm）.MTT results showed that the Ce6@F127-MOFs/H₂O₂/Light group had the strongest killing effect on pancreatic cancer cells,followed by the Free Ce6/Light group,while the Ce6@F127-MOFs/Light group basically had no killing effect on the cells.When the Ce6 concentration reached2.5μg/ml,the killing rate of pancreatic cancer cells in the Free Ce6/Light group was48.97%,the killing rate of pancreatic cancer cells in the Ce6@F127-MOFs/Light group was 16.23%,and the killing rate of pancreatic cancer cells in Ce6@F127-MOFs/H₂O₂/Light group was as high as 85.34%（P<0.0001）.The laser confocal microscope can clearly observe that Ce6@F127-MOFs/H₂O₂/Light group has a large amount of reactive oxygen species（ROS）.By analyzing the average fluorescence intensity of ROS produced by cells,Ce6@F127-MOFs/H₂O₂/Light The amount of active oxygen produced in the group was 1.88 times that of the Free Ce6 / Light group（P <0.001）.At the animal level,Ce6@F127-MOFs/Light significantly inhibited tumor growth.TNUEL staining and Ki67 staining also confirmed our hypothesis.HE staining and the change in body weight during treatment of mice reflected the biosafety of nanomedicine in vivo.Conclusion: Ce6 photosensitizer is encapsulated by metal-organic framework material and modified by surfactant F127 to enhance stability in serum.After wrapping with MOFs,the characteristics of MOFs and the H₂O₂ reaction in the tumor microenvironment can be used to improve the hypoxia state of the tumor microenvironment and generate higher levels of reactive oxygen species.Animal-level experiments have further verified the results and enhanced photodynamic therapy to kill pancreatic cancer cells.This research provides new theoretical support for many clinical and scientific researchers in sensitizing photodynamic therapy.