| In recent years,much attention has been paid to tumor immunotherapy.Studies have shown that a single tumor immune checkpoint often unsatisfactory treatment,the patient's benefit is limited,this may be due to the complexity and heterogeneity of the tumor microenvironment.In tumor microenvironment,cancer cells will "domesticated" various immune cells,become an accomplice in the development of tumors,typically aerobic glycolysis.Tumor cells secrete lactic acid through aerobic glycolysis,to suppress the function of immune cells and induce tumor-associated macrophages(TAMs)into the M2-type transformation that promotes tumor growth.In the tumor microenvironment is a state of immunosuppression,less lymphocyte infiltration,the function of lymphocytes is inhibited.Therefore,Importantly,it is demonstrated that the interaction between the tumor metabolism and immunity plays an essential role in immunotherapy,and the developed drug combination and nanoformulation can targed the multiple components in the complicated network of TIME,providing a potential therapeutic strategy.Objective:In this study,the biomimetic targeted drug delivery system was constructed to induce tumor cell immunogenic cell death to trigger tumor immune circulation and improve the effect of tumor immunotherapy through metabolic reprogramming in tumor microenvironment.Methods:Based on the above research objectives,in order to improve the bioavailability of drugs and improve the aggregation of drugs to the tumor site,we will establish a bionic targeted drug delivery system containing shikonin and JQI.Which is a lactoferrin(LF)nanoparticles(LF NPs)for tumor overexpressed low-density lipoprotein receptor-related protein-1(LRP-1)targeting for CT26 colon cancer therapy.The lactoferrin nano drug delivery system was prepared by a heat-driven self-assembly method,and the lactoferrin nanoparticles were modified with mannose(Man-LF NPs),make its can target tumor cells and the tumor associated macrophages.In this study,a series of experiments were conducted to evaluate the antitumor effects of nanoparticles,include intracellular uptake,toxicity of nanoparticles to tumor cells,tumor cell apoptosis,evaluation of immunogenic cell death and glycolysis,intracellular ROS level detection and so on.The antitumor effect in vivo was also studied.Results:The main research contents and results of this topic are as follows:1?Man-LF was synthesized and characterized by mass spectrometry.LF NPs and Man-LF NPs were constructed by a heat-driven self-assembly method,and the particle sizes,PDI and stability of the two kinds of nanoparticles were investigated.The experimental results showed that the particle sizes of the two kinds of nanoparticles were uniform and about 150 nm,and the morphology was regular and spherical with good stability.2?Cells in vitro experimental results show that the Man-LF NPs can significantly improve the uptake efficiency of CT26 colon tumor cells,its antitumor effect is superior to LF NPs,the Man-LF NPs can serve as multi-target therapy for inducing immune cell death in the cancer cells,repressing glucose metabolism,repolarizing tumor-associated macrophages,Moreover,JQ1 is a suppressor of PD-L1,and the Man-LF NPs can also work on PD-L1 checkpoint blockage.3?The results of in vivo animal experiments showed that the constructed nano-system was highly tumor-targeted and could inhibit the tumor growth of tumor-bearing mice,prolong the survival time of tumor-bearing mice,promotion of dendritic cell maturation and CD8 T cell infiltration,as well as suppression of Treg,and consequently,lead to remodeling the tumor immune microenvironment(TIME).Conclusion:Shikonin can induce immunogenic cell death in tumor cells and inhibit the glycolysis function of tumor cells.In addition,lactoferrin nanoparticles co-loaded with shikonin and JQ1 have the effect of enhancing tumor immunotherapy.Therefore,the nano-drug delivery system constructed in this study has potential tumor treatment strategies. |
PDF Full Text Request