Design And Synthesis Of Photothermal Reagents For Covalently Binding Proteins And Their Application In Tumor Photothermal Therapy

As the global population grows and ages,cancer is the leading cause of premature death and reduced life expectancy in many countries.According to the latest statistics from the World Health Organization’s International Agency for Research on Cancer(IARC)database,in 2020,the number of new cancers in China was 4.57 million and the number of cancer deaths was 3 million,both of which ranked first in the world.Interventions for cancer prevention and treatment have been incorporated into our country’s health plan.As an emerging tumor treatment method,photothermal therapy has received extensive attention due to its advantages of minimally invasive and high efficiency.The principle is that under near-infrared laser irradiation,the photothermal agent at the tumor site releases heat during the vibrational relaxation process,which in turn causes thermal damage and induces tumor ablation.In recent years,many inorganic nanomaterials and organic small molecules have been continuously developed for tumor photothermal therapy.Under the joint efforts of many researchers,great progress has been made in the development of photothermal reagents.However,due to the disadvantages of traditional organic photothermal materials such as poor targeting,easy efflux,and high laser power density required for treatment,normal tissues will still be damaged during tumor treatment.Therefore,there is an urgent need to develop more targeted photothermal reagents with fewer side effects for tumor treatment.Protein is the material basis of all life and an important part of body cells.Among them,thiol protein,as one of the most abundant proteins in cells,can realize the cell signal transduction of nitric oxide and hydrogen sulfide through post-translational modifications such as protein sulfhydryl nitrosylation and protein persulfide.Many studies have proved that these processes are closely related to the occurrence of various diseases.The latest research on cancer-related proteins has found that some proteins are involved in the occurrence,development,metastasis and recurrence of cancer.As an important molecular target for new drug design,proteins play an important role in helping to improve cancer diagnosis and treatment strategies.Therefore,by covalently binding the photothermal agent to the protein,the efflux of the photothermal agent molecule can be reduced,thereby causing the thermal damage of the protein more efficiently and enhancing the tumor treatment effect.Based on this,this thesis designed and synthesized two kinds of organic small molecule photothermal agents that can covalently bind proteins,which can effectively reduce heat loss through protein anchoring strategy and can be used to enhance the photothermal therapy of tumors.Specifically,the work includes the following two aspects:1.We propose a protein-binding strategy to design and synthesize a small molecule photothermal agent(MAL-CDYQ)for tumor photothermal therapy.MAL-CDYQ can covalently bind with thiol groups on proteins in cells,thus shortening the distance between photothermal agents and proteins,so that the heat generated can directly destroy bioactive proteins in cells,and effectively reduce heat loss and molecular efflux.At a lower power density(0.2 W/cm2),the temperature generated by MAL-CDYQ is sufficient to induce tumor cell death.The results of in vitro and in vivo experiments show that this protein binding strategy can effectively improve the effect of photothermal therapy.2.The Golgi apparatus is an important organelle regulating the physiological functions of cells.Most intracellular proteins are modified,transported and secreted in the Golgi apparatus.Therefore,destruction of the Golgi apparatus is a feasible strategy to inhibit tumor growth.In this thesis,a novel photothermal agent(GA-PRT-PT)for Golgi targeting tumor photothermal therapy was prepared by modifying benzosulfonamide structure and maleimide derivative on NIR molecular dye.GA-PRT-PT can be fixed to sulfhydryl proteins by covalent binding,which increases the accumulation of photothermal agents in Golgi apparatus.The concentration of heat produced by photothermal agent under laser irradiation destroys Golgi apparatus,resulting in Golgi apparatus dysfunction,and finally induces apoptosis.In vivo experiments show that the photothermal agent can effectively kill cancer cells by thermal ablation.