Screening Of Materials For Inducing Immunogenic Cell Death And Their Applications For The Treatment Of Glioma

Tumor is a global disease that seriously threatens national health.Although the current most effective immunotherapy has achieved great clinical success,its treatment in brain tumors still faces great challenges.The complex physiological and pathological barriers of glioma(GBM)severely limit the delivery of drugs and the anti-tumor immune effect.In response to the above problems,this thesis screened the materials based on the dendrimer PAMAM and found that the biomaterial D47 can induce strong immunogenic cell death(ICD)and verified its ICD effect on different cell lines.Then further explored the cellular uptake and mechanism of endocytosis of different materials by cells.Based on D47,the ANG peptide that can bind to the low-density lipoprotein receptor-related protein 1(LRP1)which is highly expressed on the surface of brain capillary endothelial cells was used to modify D47 to enhance the effect of passing through the blood-brain barrier(BBB).The specific research contents were as follows:1.By detecting the changes in the expression of CALR on the cell surface,comparing the ICD effect induced by different structural materials in the material library,D47 biomaterial was found.Its unique structure enables it to induce a strong ICD effect.It could cause a significant expression of CALR on the cell surface and the release of ATP and HMGB1.Then its ICD effect was verified again in mouse and human cell lines,respectively.Secondly,in order to study the mechanism of ICD effect produced by different functional materials,we further explored the uptake of materials with different ICD effect and the mechanism of these materials being internalized by cells.At the same time,a preventive vaccine experiment was established to study the ICD effect of D47,after treatment with D47,it can effectively inhibit tumor growth.2.Used the above material D47 which has the effect of inducing ICD,and linked with ANG peptide to obtain APD nanoparticles.In vitro experiments have shown that APD could be taken up by endothelial cells and glioma cells,and by constructing an in vitro BBB model,it has been verified that APD can pass through the BBB and be taken up by tumor cells.By detecting the damage-associated molecular patterns released by tumor cells and the ability to promote the function of APCs after treatment with APD,the ICD effect was further verified.In vivo experiments constructed subcutaneous and intracranial in situ GL261 glioma tumor-bearing mouse models and combined with immune checkpoint inhibitor PD-1 antibody for anti-tumor therapy.APD showed a strong therapeutic effect and increased CD8~+T cells infiltration in the tumor.