Multifunctional Palladium-based Nano-enzyme Combined Optical Therapy With Tumor Microenvironment Control Strategies For Colorectal Cancer Combined Treatment

Colorectal cancer(CRC)is still one of the diseases with highest morbidity and mortality in the world.Its symptoms are insidious,easy to metastasize and spread,posing a serious threat to human life and health.The efficacy of traditional treatment methods for colorectal cancer is very limited,it is needed to further research and develop effective medical treatment methods.Multi-functional drugs synthesized based on nanotechnology can achieve a variety of advantages as needed,such as drug tracking,drug-specific targeting,and drug controlled release at the disease site,and high biocompatibility,etc.,which can significantly improve cancer diagnosis and Treatment efficiency.In recent years,the general trend of nanomedicine research has shifted from monotherapy to combination therapy with multiple treatment strategies.Single administration can realize multiple treatment methods and achieve the effect of "1 + 1 > 2",which is a new and highly effective cancer treatment strategy.In this project,two types of functionalized inorganic palladium nanosystems were synthesized,which used their broad near-red light absorption capacity and CAT-like catalytic activity to inhibit cancer cell survival through photothermal therapy and chemodynamic therapy(CDT).In addition,the tumor microenvironment control strategy was combined to efficiently fight against primary tumor and metastasis.The main contents of this article are as following:In chapter 1,the introduction mainly introduces the current status of cancer diseases,the anti-tumor application progress of nano-medicines treatment strategies,and the correlation between tumor microenvironment and immunotherapy strategies.The potential application of nano-medicine in combination treatment between traditional therapy and immunotherapy is also further elaborated.At the end of the introduction,the research purpose and significance of the topic is pointed out.In chapter 2,a new therapeutic system(Pd-Dox@TGMs NPs)that can effectively trigger ICD by combining chemotherapy and photothermal therapy was designed.The nanosystem was fabricated by integrating doxorubicin(Dox)and a photothermal reagent palladium nanoparticles(Pd NPs)into amphiphile triglycerol monostearates(TGMs),which showed specific accumulation,deep penetration,and drug controlled release in response to the tumoral enzymatic microenvironment.It was proved that codelivery of Dox and Pd NPs not only effectively killed CT26 cells through chemotherapy and photothermal therapy,but also promoted the release of dangerous signaling molecules,such as high mobility group box 1,calreticulin,and triphosadenine,improving the immunogenicity of dead tumor cells.The effective ICD induction ability mediated by Pd-Dox@TGMs NPs boosted the PD-L1 checkpoint blockade effect,which efficiently improved the infiltration of toxic T lymphocytes at the tumor site and showed excellent tumor treatment effects to both primary and abscopal tumors.Therefore,this work provides a simple and effective immunotherapeutic strategy by combining chemical-photothermal therapy to enhance immune response.In chapter 3,Ultra-small Pd NPs were prepared by carbon monoxide reduction.Hyaluronic acid and mannose molecules were modified on the surface of the palladium nanocarrier to prepare Pd-HA + Pd-Man@R837 NPs.The prepared functional nanoparticles have dual targeting capabilities for both tumor cells and macrophages.Utilizing the highly efficient CAT-like enzyme activity of ultra-small Pd NPs to catalyze the production of ROS,which directly causes the death of colorectal cancer cells through CDT action;In addition,macrophage polarization regulator,imiquimod molecule,polarizes tumor-associated macrophages with M2 phenotype in the microenvironment into anti-tumor M1 types,activating the immune efficacy of macrophages to inhibit tumor growth.In vitro and cell-level experiments have demonstrated that the functional nanosystem exhibits high ROS-inducing ability and tumor cell lethality.This work is a combination of traditional chemodynamic therapy and macrophage polarization strategy immunotherapy,providing new ideas to fight against tumor development.