Application Of Metal-organic Molecular Cages In Tumor Therapy

Cancer is the second leading cause of death in the world and has a major impact on human life and health.In recent years,ROS-based therapies have been recognized as effective strategies for tumor suppression due to the low resistance of ROS to cells and the strong oxidative lethality.Among them,photodynamic therapy(PDT)base on¹O₂and chemodynamic therapy(CDT)based on·OH are widely used due to their strong oxidation.However,the clinical application of PDT and CDT is severely limited by lack of oxygen in tumor cells,insufficient utilization due to the photosensitizer aggregation,insufficient drug penetration,and low amount of H₂O₂in tumor.Therefore,it is of great significance to develop efficient PDT photosensitizer and CDT preparation for cancer treatment.Metallacage is a kind of cage-like compound formed by self-assembly of metal ions and organic ligands through coordination bonds.By adjusting metal ions and ligands,a stable,rigid,zero-dimensional metallacage with independent cavity.Attributed to the appropriate nano-size,adjustable structure and low biotoxicity,metallacages are widely used in drug delivery,biomedicine,biosensing and other fields.In this thesis,we synthesized two nanoplatforms based on metallacage to study their therapeutic effects on breast cancer tumors.The main work of this paper is as follows:Part one:Porphyrin-based metallacage and hyaluronidase for enhanced photodynamic therapyIn this part,we synthesized porphyrin-based metallacage(PM)with photosensitive porphyrin as ligand and was coated with hyaluronidase(HAase)and DSPE-mPEG to form nanoparticle PM@HAase-mPEG for enhanced PDT therapy.Solution and cell experiments proved that PM could avoid the aggregation of porphyrin single in aqueous solution and induce porphyrin quenching,improve the utilization rate of photosensitizer and increase the production of ¹O₂.The results of cell experiments showed that HAase could effectively increase drug uptake,and slice results of mice after therapy showed that HAase could significantly promote the generation of blood vessels in tumor tissues and relieve hypoxia.In vitro and in vivo experiments both have proved that PM@HAase-mPEG has good biocompatibility,prominent PDT treatment effect,obvious inhibition effect on breast cancer tumor cells.Part two:Iron-based metallacage and oxaliplatin for chemotherapy combined with enhanced chemodynamic therapyThis part of the work is an improved research based on our former study.In this part,we synthesized water solvable tetrahedral Fe-based metallacage(Fe-1)with Fe²⁺as the apex and pyridine imine with propanediol as ligands.Fe²⁺ions with six saturated coordinated could catalyze fenton reaction to produce hydroxyl radicals indicating that Fe-1 is able to act as CDT agent.Nano-particle Fe-1@OXA-PEG was formed by ultrasonic self-assembly of Fe-1 with amphiphilic copolymer PEG-COOH2000 and chemotherapy drug OXA,combining CDT and chemotherapy(CT)to achieve the combined treatment.Meanwhile,OXA could not only acts as anti-tumor drugs but also it activates the intracellular nicotinamide adenine dinucleotide phosphate oxidase(NOX)and superoxide dismutase(SOD)to produce H₂O₂,which is the substrate of fenton reaction,,thus enhancing CDT and realizing the enhanced combination therapy of CDT and CT.In vitro and in vivo experiments results show that Fe-1@OXA-PEG has little biological toxicity,synergistic enhancement of therapeutic effect,significantly inhibit the growth of tumor cells,is a potential anticancer drug.