Construction Of Prussian Blue-based Nano Delivery System For Application Of Hepatocellular Carcinoma Immunotherapy And Photothermal Therapy

Surgery is still the most effective way to improve the survival rate of hepatocellular carcinoma(HCC)patients,but the higher recurrence rate after surgery seriously affects the efficacy.With the understanding of the tumor microenvironment(TME),it has been discovered that the tumor-associated macrophages(TAM)in TME are highly infiltrated in various tumor tissues,and are associated with tumor cell growth,invasion and angiogenesis.More and more data show that there is a close relationship between TAM infiltration and the poor prognosis of tumors.Thus,there is a broad prospect for the development of targeted TAM treatment measures.In this paper,we constructed a new type of nanoparticle that targets the CD47-SIRPα and MCSF-CSF-1R signal axes to achieve regulate macrophage phenotype,targeting the tumor microenvironment-BLZ945@PB/Anti-SIRPα NPs.Characterized by ultraviolet-visible light absorption spectroscopy,fourier transform infrared spectroscopy,malvern zetasizer nano ZS90,and polyacrylamide gel electrophoresis.The results show that the prepared BLZ945@PB/Anti-SIRPα NPs are uniform in size,good dispersion,the size is 70 nm.The preparation has excellent photothermal conversion ability and p H sensitivity,it can realize the responsive release of related drugs.It also has catalase activity and can alleviate the hypoxia characteristics of the tumor microenvironment.The SIRPα antibody is modified on the surface of nanoparticles to achieve the targeting effect on macrophages,while blocking the CD47-SIRPα signal axis,combined with BLZ945 drug and photothermal therapy to play a synergistic therapeutic effect,realizing the conversion of TAM phenotype.The formulation has good stability within 48 hours and can be used for subsequent experiments.The prepared nanoparticle chimeric fibrin gel BLZ945@PB/Anti-SIRPα Gel has excellent toughness and elasticity,swelling capacity,hemostatic performance and the ability of in vitro degradation.In vitro experiments successfully constructed macrophages with M1 and M2 phenotypes.Related results show that BLZ945@PB/Anti-SIRPα NPs have excellent targeting,phenotypic switching and lysosomal escape capabilities.Cytotoxicity experiments showed that neither the carrier nor the preparation had obvious toxicity.The supernatant after phenotypic conversion of macrophages has a certain inhibitory effect on the growth,invasion and metastasis of HCC cells.In vivo experiments show that BLZ945@PB/Anti-SIRPα NPs can achieve long circulation in vivo and have excellent targeting ability.After treatment,tumor volume,organ index,immunofluorescence and other results all show that the preparation can activate anti-tumor immunity to achieve killing effect on tumor cells by reversing the TAM phenotype.During the treatment,the curve of body weight and the hematoxylin-eosin staining results of major organs show that the preparation has good biological safety.In summary,BLZ945@PB/Anti-SIRPα NPs have excellent ability of regulation TAM phenotype,which can effectively change the immunosuppressive microenvironment in the tumor.Combined with photothermal therapy can play a synergistic effect and provide new ideas to prevent postoperative recurrence and metastasis of liver cancer.