Study On The Photodynamic Immunotherapy Of Iron(?)-Based Metal-Organic Framework Nanomaterial

In recent years,the incidence of cancer is increasing globally,which seriously endangers people's life and health.Traditional treatments for cancer include chemotherapy and radiation in combination with surgery.However,due to the short of targeting ability,these treatments kill tumor cells while exerting adverse side effects on the normal cells.That seriously limits their therapeutic effects.Photodynamic immunotherapy is a new class of tumor therapy based on light response.Photodynamic immunotherapy mainly consists of three components: light,photosensitizer and oxygen.Photoactivated photosensitizers can produce cytotoxic reactive oxygen species from oxygen in photodynamic therapy.Reactive oxygen species directly destroy tumor tissues and induce apoptosis.In immunotherapy,reactive oxygen species further induce immunogenic cell death,trigger dendritic cell maturation and activate host immune system.Then immune system precisely kills tumor cells and inhibits tumor growth.The merits of photodynamic immunotherapy,such as high selectivity,low toxicity and less side effects,have effectively solved the problems of traditional treatment methods,and have potential for clinical application.However,photodynamic immunotherapy still faces some challenges,especially hypoxia in the tumor microenvironment.Hypoxia in the tumor microenvironment not only restricts the production of reactive oxygen species under photoactivation,but also promotes the production of abnormal blood vessels with uneven distribution around the tumor.Abnormal blood vessels prevent immune cells from entering the tumor tissue and inhibit the in situ proliferation of immune cells.Thus hypoxia inhibits both photodynamic therapy and immunotherapy.Catalytic decomposition of hydrogen peroxide is an effective method to relieve tumor microenvironment hypoxia.Excessive hydrogen peroxide molecules exist in the tumor microenvironment and inside tumor cells,which can in situ produce oxygen by Fenton-like reaction,thus solving the problem of hypoxia in photodynamic immunotherapy.Metal-organic framework(MOF)nanomaterials are porous nanomaterials which are consisted of metal ions and organic ligands.MOF nanomaterials enable the stable existence of metal ions and organic ligands in vivo,and distribute them in tumor tissues through passive targeting.Among them,iron(?)-based MOF has prominent advantage in cancer treatment because iron(?)can catalyze hydrogen peroxide to produce oxygen by Fenton-like reaction.By assembling ferric ions and organic photosensitizer molecules into MOF nanomaterials,hydrogen peroxide can be catalyzed in situ to produce oxygen in tumor tissue,and then reactive oxygen species can be produced by photosensitization of photosensitizers under light,leading to efficient photodynamic immunotherapy.In this work,we synthesized iron(?)-based metal-organic framework nanomaterials(Fe-MOF)using ferric ions and porphyrin derivatives to relieve hypoxia in the tumor microenvironment and promote the generation of reactive oxygen species and anti-tumor immunity in mouse tumor cells.We further explored the growth inhibition effect and photodynamic immunotherapy effect of Fe-MOF on tumor-bearing mice.We finally successfully activated the immune response in mice and realized the photodynamic immunotherapy in vivo.The main contents are as follows:(1)We successfully synthesized Fe-MOF with uniform size and good dispersion by solvothermal method.The transmission electron microscopy image shows that Fe-MOF is fusiform.We further characterized its chemical structure by UV-Vis absorption spectroscopy,X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy,confirming that ferric ions and porphyrin derivatives were successfully assembled into MOF.In addition,the oxygen and reactive oxygen species generated by Fe-MOF in the simulated tumor microenvironment and in tumor cells were detected by dissolved oxygen analyzer and reactive oxygen species probe.The results showed that Fe-MOF could produce large amounts of oxygen by Fenton-like reaction in simulated tumor microenvironment and tumor cells,as well as reactive oxygen species under light.By staining of cells,we confirmed that the reactive oxygen species produced by Fe-MOF can effectively kill tumor cells.The results showed that the Fe-MOF can solve the problem of hypoxia in tumor tissue and is expected to activate the immune system to kill tumor tissues in photodynamic immunotherapy.(2)We further investigated the effects of Fe-MOF on tumor growth,normal organs and the activation of immune cells in breast cancer mice.The tumor inhibition effect of Fe-MOF was evaluated by measuring the volume and mass of tumor in mice.The results showed that Fe-MOF successfully reduced the volume and mass of tumor in mice.The stimulation to immune system was studied by flow cytometry.The results showed that T lymphocytes and dendritic cells increased,while regulatory T cells and myeloid-derived suppressor cells participating in the immunosuppression decreased,indicating that anti-tumor immunity was successfully induced.The tissue sections were stained with hematoxylin and eosin to investigate the structural morphology of tumor cells and the effect of Fe-MOF on normal tissues and organs.The results showed that Fe-MOF could effectively destroy tumor tissues,but had little effect on normal tissues of mice,indicating that Fe-MOF has good biocompatibility and excellent response ability of tumor microenvironment.These results altogether confirmed that Fe-MOF effectively kills tumor cells,simultaneously activates the anti-tumor immunity and realizes immunotherapy in mice.And Fe-MOF has almost no side effects on normal tissues.The Fe-MOF is expected to play an important role in clinical treatment due to its low toxicity and high efficacy in tumor therapy.