The Study Of Efficiency And Mechanism Of Enhanced Anti-tumor Immune Response By Aluminum Nanoparticles

Background and Objective:With the rapid growth of malignant tumor patients in the world,the exploration of cancer treatment has become a research hotspot.The clinical treatment of cancer is changing from traditional surgical resection,radiotherapy and chemotherapy to new targeted treatment and immunotherapy.There are some limitations of traditional radiotherapy and chemotherapy,such as side effects and high drug resistance;Targeted therapy is a great breakthrough during the development history of cancer treatment,however,the universality of targeted therapy is restricted by the lack the driver genes and therapeutic targets in some kind of cancer;Accompany with the commercialization of immune checkpoint inhibitors,immunotherapy has become a new hope and provided a new strategy of altering the tumor immunosuppressive microenvironment for cancer treatment.Although immunotherapy has achieved good results in the treatment of some types of tumors,the overall response rate is still low,and immune-related adverse events are obvious,which become the main obstacle of tumor immunotherapy.Therefore,how to activate anti-tumor immune response and reduce side effects is the key to improve the efficacy of tumor immunotherapy.Effective uptake,processing and presentation of tumor antigens by antigenpresenting cells to killer T lymphocytes,and activation of tumor antigen-specific T lymphocytes are the key to enhancing tumor immune response.Since Glenny applied diphtheria toxin-aluminum salt sediment as a vaccine to prevent human diseases in 1926,biologics containing aluminum have been widely used as immune activators of antigen-presenting cells.In long-term research and clinical practice,high safety and effective immune enhancement effect of aluminum has been widely recognized.And it is the first metal preparation approved by the US Food and Drug Administration(FDA),as a recognized humoral immune response inducer.However,the traditional aluminum biologics is a mixture of micron particles of different sizes,which is basically unable to induce cellular immune response,limiting its application in the field of tumor therapy.In recent years,nanomaterials have developed rapidly in medicine and breakthroughs have been made in improving drug bioavailability,extending drug half-life,targeted delivery and controlled release.The continuous development of nanotechnology provides a way to develop novel nano-aluminum biologics.Some studies have shown that aluminum salt nanoparticlas can activate cellular immune response,and show anti-tumor effect,which brings new strategies for developing and expanding the application range of aluminum nanomedicine.Methods:A kind of novel spherial aluminum nanoparticles with good-dispersity and the particle size could be control by adjusting the preparation temperature.Firstly,the cytotoxicity of aluminum nanoparticles was verified and the biosafety of aluminum nanoparticles was verified by biodistribution,serum biochemical index detection and histopathology.Secondly,by comparing the immune enhancement effects of different sizes of aluminum nanoparticles,the optimal particle size was screened.Then,the changes in the immune system caused by aluminum nanoparticles were explored through the analysis of mouse lymph nodes,spleen and peripheral blood.And by analyzing the tumor microenvironment after treatment,the mechanism of enhancing the anti-tumor effect of aluminum nanoparticles in immunotherapy was explored.Finally,a mouse melanoma model was used to evaluate the effect of aluminum nanoparticles on enhancing the anti-tumor effect of immunotherapy.Results:1.A kind of novel spherical aluminum nanoparticles with good-dispersity was successfully prepared and the particle size could be control by adjusting the preparation temperature.2.It has been proved that aluminum nanoparticles have good biocompatibility and biosafety,and can not cause accumulation and tissue damage in vivo.3.Aluminum nanoparticles could increase antigen uptake of DCs and promote DCs maturation and cross-antigen presentation.4.The size of aluminum nanoparticles could affect the maturation and activation of antigen presenting cells,the intensity of immune response in draining lymph nodes,and the antitumor effect.The optimal particle size for immunoenhancement is 190 nm.5.In the mouse melanoma model,aluminum nanoparticles showed strong immune-enhancing effects,which inhibited tumor formation and maintained long-term tumor-specific immune memory.Combined with anti-PD-1 antibody,aluminum nanoparticles could enhance the anti-tumor effeciency of tumor immunotherapy.6.The aluminum nanoparticles could activate the immune cells in the lymph nodes and spleen,initiate specific cellular immune responses,and regulate the tumor immunosuppressive microenvironment,increasing the proportion of CD8+ T lymphocytes and reducing the proportion of inhibitory immune cells(Tregs and MDSCs).Conclusion:A kind of novel spherical aluminum nanoparticles with good-dispersity were successfully prepared by chemical synthesis.The particle size could be control by adjusting the preparation temperature.The optimal particle size for immunoenhancement is 190 nm.By regulating lymph node,spleen and peripheral blood immune system,promoting DCs cross-antigen presentation,activating CD8+ T cell immune response,and reversing tumor immunosuppressive microenvironment,aluminum nanoparticles could enhance anti-tumor effeciency of tumor immunotherapy.The combination of aluminum nanoparticles and anti PD-1 antibody in the treatment of mouse melanoma showed synergistic anti-tumor efficiency,providing a safe and efficient strategy for improving the efficacy of tumor immunotherapy.