Study On The Mechanism Of In Situ Injectable Hydrogel Drug-loading Inducing Tumor Cell Death And Therapeutic Application

Cell death includes programmed cell death and necrosis.With the continuous deepening of research,the continuous discovery of many new methods of death has updated people’s understanding of the concept of cell death.In recent years,the traditional chemotherapeutic drugs that can cause immunogenic cell death also provide a new strategy for tumor treatment.Melanoma is one of the most aggressive tumors in the skin.The incidence has been increasing in the past few years,but traditional treatment methods are limited,and immunotherapy seems to be a feasible treatment method.In order to reduce the side effects caused by traditional drug delivery methods and enhance the body’s immune killing effect on tumor cells,we have developed for the first time an in situ injection hydrogel that can simultaneously deliver doxorubicin(Dox)and imiquimod(R837)The drug delivery system is used for the coordinated treatment of melanoma.First,a rotational rheometer was used to characterize the mechanical properties and stability of the hydrogel,and to determine the optimal dosage of the hydrogel and the drug.It was found that the co-delivery system effectively inhibited the growth of melanoma both in vitro and in vivo.Further studies have shown that the co-delivery system can lead to the death of immunogenic cells and the activation of dendritic cells,followed by the activation of T lymphocytes.In conclusion,this co-delivery system has been shown to directly induce melanoma cell death and at the same time activate the immune system to further kill the tumor,which indicates the possibility of targeted tumor therapy.In addition,the co-delivery system also induced other death modes,including iron death and parp-1-dependent death.Therefore,the mechanism of other death modes induced by chemotherapeutics should be further explored.AKT participates in a variety of cellular pathways and plays an important role in the pathogenesis of many types of tumors.Targeted inhibition of AKT inhibits tumor growth by inducing cell apoptosis,this conclusion has been confirmed.However,there is little research on whether other methods of cell death play a role in it.In our research,we found for the first time that targeted inhibition of AKT induces PARP-1-dependent cell death(parthanatos)and inhibits tumor growth.Studies have found that targeted inhibition of AKT causes cell apoptosis and also causes PARP-1-dependent cell death.In immunofluorescence experiments,the massive aggregation of PAR polymers also confirmed the occurrence of PARP-1-dependent cell death,and the addition of PARP inhibitors inhibited the production of PAR polymers.All in all,our findings prove that AKT inhibition induces parthanatos,which can be considered as a new potential cancer treatment strategy.