Phototherapy-triggered Immunotherapy For The Application In Cancer Treatment

In recent years,immunotherapy has achieved phased results in the field of anticancer therapy,and these results have inspired researchers to conduct further research on tumor immunotherapy.Among them,the most research and the widest range go to immune checkpoint blockade therapy.This is because immune checkpoint blockade therapy reverses the state of immunosuppression in the tumor microenvironment by targeting certain proteins through inhibitor drugs and blocking the link between the immune system and tumor cells.In this process,cytotoxic T lymphocytes are abundantly recruited in the tumor area,and they re-recognize and kill the tumor cells,thereby enhancing the anti-tumor effect.However,due to the innate features of immunotherapy,immunotherapeutic drugs only produce an ideal therapeutic result on few patients.Some patients tend to have serious immune inflammatory reactions after taking the drugs,which even endanger their lives.Moreover,several FDA-approved monoclonal antibodies for immunotherapy are expensive and are often unacceptable to most patients.Therefore,finding efficient and accurate immunotherapy strategies is significant.As a novel treatment in the field of anticancer therapy,phototherapy has been favored by researchers because of its minor wounds,high temporal and spatial selectivity,and few side effects.With the booming field of nanomaterials,materials can often be varied and modified according to their needs.Therefore,based on the characteristics of phototherapy,we have designed two phototherapy-triggered immunotherapy systems for the anticancer therapy.The details are as follows:In the first chapter,we gave a brief overview of photodynamic therapy,photothermal therapy,and immune checkpoint blockade therapy.It mainly introduces some strategies for enhancing the therapeutic effect of photodynamic therapy and photothermal therapy in anticancer therapy,and the advantages and specific applications of immunotherapy combined with nanomaterials.In Chapter 2,we designed a chimeric peptide PpIX-1MT based on photodynamic therapy.We used apoptotic enzyme-sensitive peptide sequence "DEVD" as a bridge to link photodynamic therapy to the IDO small molecule inhibitor 1MT.The chimeric peptide could form nanomicelles in PBS,and reach the tumor region by the EPR effect,and is enriched and retained in the tumor region.Then PpIX produces ROS and induces tumor cell apoptosis by exogenously controlled illumination.At this moment,the activated apoptotic enzyme could cleave the IDO inhibitor 1MT from PpIX-1MT,and then the downstream pathway of IDO is blocked.The CD86 and CD8 positive cells in the tumor area are abundantly recruited,and the antitumor immunological activity is activated.It is worth mentioning that we constructed a lung metastasis model by intravenous injecting CT 26 cells.According to the anti-tumor results in vitro and in vivo,the experimental group treated by PpIX-1MT and illumination could not only inhibit the growth of the primary tumor,but also achieve an outstanding inhibitory effect on the lung metastasis.In the third chapter,we designed and synthesized the nanomaterial AuNC-Apt based on photothermal therapy.We used a gold nanocage as the photothermal part of the material,and connected a single strand of DNA to it via a gold-sulfur bond.By the principle of base pairing,another aptamer Apt having a PD-1 targeted and immunotherapeutic effect links the single-stranded DNA on the surface of the gold nanocage to form a double helix structure.Here we designed the melting temperature of the complementary segments of the helix structure to 43 °C.Thus,through the photothermal effect of gold nanocage,AuNC-Apt could release the aptamer Apt in the tumor region by melting of the helix structure and the Apt could target the PD-1 protein expressed on T lymphocytes.While AuNC-Apt is enriched and retained in the tumor area by the EPR effect.Therefore,our material AuNC-Apt is characterized by the dual targeting of tumor cells and lymphocytes.In the malignant melanoma model,the tumorinhibiting effect of the experimental group treated with AuNC-Apt and illumination was significant,and the results of ELISA and immunofluorescence staining showed that the anti-tumor immune activity was significantly activated in the tumor area.