Shellable Liposomal Vesicles For Photo-immunotherapy Of Colon Cancer

In recent years,the mortality rate of malignant tumors has increased rapidly,and it has become the number one killer of people's health all over the world.There are many therapy treatments in clinic,mainly including surgical resection,chemotherapy and radiotherapy,but these treatments are useless for,and are helpless for the metastasis and recurrence of tumors.The emergence of cancer immunotherapy provides solutions to these problems.Tumor immunotherapy can significantly prolong the survival of patients and even cure them by regulating the human immune system to spontaneously identify and kill tumor cells.However,the low immune response rate and immunosuppression of tumor immunotherapy in solid tumors severely limit its clinical effect.Therefore,how to improve the immune response of tumor cells and alleviate the immunosuppression of tumor cells has become an urgent problem in immunotherapy.Herein,we combine photodynamic therapy with immunotherapy to induce the production of ICD,enhance the immunogenicity of tumor cells and improve the immune response of tumors.At the same time,we can inhibit the metabolism of tryptophan by giving IDO inhibitors,reduce Tregs in tumors,restore the vitality of cytotoxic T cells and relieve the immunosuppression.We hope to eliminate cancer cells and inhibit the recurrence of cancer cells with this dual therapy strategy.At first,we constructed an MMP2-responsive immunoliposome drug delivery system.The shellable PEG photosensitizer was synthesized as a long-circulating shell of liposome system.Only when there is a high level of MMPs in the tumor site,the PEG shell could fall off and increase the uptake of tumor cells,thus retaining in the tumor site.At the same time,the strategy of coupling small molecule inhibitors to phospholipids via a disulfide bond can greatly increase drug loading and structure stability,reduce drug leakage,and make local release in tumor cells.The characteristics of these two materials,through the perfect combination of liposomes,can achieve the gradual release of drugs in tumor tissue.we found that the photosensitizer can produce a large amount of reactive oxygen species in the tumor site after the treatment of 671nm near infrared light,which can cause oxidative stress of the tumor cells,induce immunogenic death of the tumor cells,generat damage-related molecular patterns(DAMPs),promote the maturation and antigens cross-presentation of DC cells,promote the proliferation and tumor infiltration of CTLs,turn the cold tumors into hot tumors.NLG-919,as a powerful IDO inhibitor,can greatly reduce the activity of IDO enzymes,prevent tryptophan metabolism,provide adequate food for CTLs,and decrease Tregs recruitment of kynurenine and relieve immune suppression.ENP-919showed great tumor killing and recurrence inhibiting ability in both CT26 and 4T1models in Balb/c mice.The proportion of IFN-?~+CD8~+T cells in CT26 tumors was 30times higher than saline group,but The proportion Tregs decreased 90%,both of these confirmed the fact of tumor immune activation and immune suppression relief.The above work focus on the combined therapy of activating immune recognition and getting rid of immunosuppression,using nanocarriers to efficiently deliver photosensitizers and IDO small molecule inhibitors to the tumor site,eliciting the immune recognition and response through photodynamic stimulation,and improving the microenvironment of immunosuppression at the tumor site through inhibitors,thus providing a simple and efficient strategy for clinical immunotherapy.