Nanomedicine Delivery System For Tumor Immunotherapy

With more and more serious ecological environmental pollution,accelerated aging process and poor lifestyles,the risk of people suffering from tumors is gradually increasing,which poses a huge threat to the life and health of human.Currently,there are three conventional methods for treating tumors: surgical resection,chemotherapy and radiation therapy.However,these traditional methods are difficult to remove tumor cells completely,which bring hidden dangers to tumor recurrence and metastasis.Tumor immunotherapy refers to the specific elimination of cancer cells by activating immune cells in the body.This therapy has the advantages of strong specificity,longlasting effect and less side effects,and is considered to be the last resort for treating tumors.T cells are the most effect immune cells to kill tumor cells in the immune system.How to effectively activate T cells is the core issue in tumor immunotherapy.The activation of T cells requires three signals from antigen presenting cells(APC): antigen signal,costimulatory signal and cytokine signal.The main kinds of APC are dendritic cells(DC),macrophages,and B cells.Among them,DC is the most professional antigen-presenting cell to activate naive T cells,which can capture,process,and present antigens.Therefore,it is very important to stimulate the body's tumor-specific immune response by regulate DC differentiation and function.At present,the DC vaccine used in clinical practice is mainly by culturing and activating DC extracted from the patients,and reinjecting it back after activation.Although this type of DC vaccine has achieved certain results,it has limitations due to their high costs,large batch-to-batch differences,and complex processes.Meanwhile,the DC reinjected into the body also has problems such as weakened migration ability and antigen presentation ability,which limits its practical application to a certain extent.The development of nanovaccine that can target DC in vivo is expected to improve the effect of tumor immunotherapy and promote the clinical application of DC vaccine.Although tumor immunotherapy has received widespread attention,a large number of clinical trials have confirmed that immunotherapy has little effect in most cancer patients.Studies have found that the clinical effects of immunotherapy are inseparable from the tumor microenvironment.First,the high density and high interstitial pressure inside the tumor limits the penetration of external drugs.Second,during the occurrence and development of tumors,an immunosuppressive microenvironment is gradually formed,which not only inhibits the effect of anti-tumor immune cells,but also induces some immune cells polarized into a tumor-promoting phenotype.Therefore,in order to improve therapeutic effect,new tumor immunotherapy needs to overcome the barrier of high tumor density and high interstitial pressure,break the influence of the immunosuppressive microenvironment,and help the body rebuild its anti-tumor immunity.Based on the above background,in this thesis,we have developed a series of nanomedicines with targeted functions to solve the problems in current tumor therapy and immunotherapy,and successfully applied them to tumor immunotherapy.In order to avoid the current problems in the preparation of DC vaccines,in Chapter 2,we constructed a DC-targeted nanovaccine and investigated its targeting ability and immune effect in vitro.Experimental results show that the nanovaccine can target immature DC and can effectively activate the maturation of DC.Subsequently,in Chapter 3,we continued to investigate the targeting ability and immune effect of the nanovaccine in vivo by constructing a mouse model.Experimental results show that the nanovaccine can still target DC in vivo and has a good immunotherapy effect.Taking into account the impact of tumor microenvironment on immunotherapy,in Chapter 4,we constructed a macrophage-hitchhiked nanomeidicine delivery system to overcome the tumor's high-density and high-osmotic pressure barrier to improve the intratumoral accumulation of nanomedicine.The experimental results show that the apoptotic bodies wrapped with gold nanorods can be specifically engulfed by macrophages,and thus be efficiently carried into the tumor spheroid,which proves the feasibility of the macrophage-hitchhiked strategy.In Chapter 5,we constructed tumor models,tumor metastasis models,and tumor recurrence models on mice to investigate the effect of macrophage-hitchhiked strategy in tumor immunotherapy.Experimental results show that this macrophage-based nanomedicine delivery system still has the ability to target macrophages in vivo,and achieves effective diffusion inside the tumor.In addition,with the excellent photothermal properties of gold nanorods,macrophagehitchhiked strategy can break the tumor immunosuppression environment,promote tumor immune response,and have obvious effects on inhibiting tumor growth and prognosis.