Construction And Application In Tumor Therapy Of Stimulus-responsive Covalent Organic Frameworks

Nanodrugs delivery systems can enhance the cellular uptake of drugs through cytokinesis and passively target tumor sites by using enhanced permeability and retention effect（EPR）.However,nanodrug delivery systems also suffer from premature drug release and systemic toxicity.The development of stimulus-responsive drug delivery systems can address these drawbacks of drug delivery systems.Stimuli can be classified into exogenous and endogenous stimuli depending on the source.The structure of the nanocarrier collapses under the action of the stimulus,and precise drug release at the tumor site can be achieved for the purpose of targeted therapy.The interaction between the drug molecule and the nanocarrier is weakened after the bond breaking of the drug-carrying platform to improve the drug release rate.The inherent characteristics of covalent organic frameworks（COFs）,such as high specific surface area and ultra-high porosity,allow them to have ultra-high drug-loading capacity and become the star material for drug delivery systems.Similar to other drug delivery platforms,the interaction between drug molecules and COFs carriers limits the drug release and reduces drug utilization,but the richness and high designability of COFs molecular structural units allow us to introduce the active site into the framework of COFs and release the active site under the action of external or/and internal stimuli so that the fracture of COFs framework can induce drug release and improve drug utilization.Such a design will improve drug utilization and reduce the possibility of drug resistance in cells due to insufficient release of the drug in the early stage.Based on this,this thesis investigates the design and synthesis of stimulus-responsive covalent organic frameworks and their applications in antitumor,with the following four main components.Ⅰ.The first reactive oxygen-responsive COF containing a thioketone-bonded active site was synthesized by a solvothermal method consisting of a porphyrin photosensitizer and a thioketone-bonded reactive oxygen species-responsive molecular building blocks.The composite nanodrug with high drug loading capacity was obtained after its own nanocrystallization and loading of DC＿AC50.Under the irradiation of near-infrared light,the multifunctional nanodrug has excellent singlet oxygen（¹O₂）production ability and exhibits certain photodynamic therapy（PDT）effect.Meanwhile,the ¹O₂ generated by COF itself under light conditions can break thioketone-bonded in the framework leading to the fracture collapse of the COF,achieving the rapid,controlled and efficient release of DC＿AC50 triggered by NIR light and responsive by ROS at the tumor site.The released DC＿AC50 disrupts copper homeostasis in the tumor environment by binding to Atox1and CCS to increase ROS levels for sustained drug release in the tumor.DC＿AC50 also acts as a chemotherapeutic agent.Successful stimulus-responsive chemotherapy/PDT combination therapy against HT-1080 cells in vivo and in vitro.Ⅱ.The first porphyrin-NCOF containing disulfide bonds and metal-free porphyrins bonded by imine bonds was synthesized under solvothermal conditions using metal-free porphyrins and disulfide-containing diamines as molecular building blocks to achieve efficient loading of 5-fluorouracil（5-Fu）.The exchange reaction between disulfide bonds in NCOF and GSH reduces the amount of reducing substances in cells and can improve the effect of PDT treatment.The difference in GSH expression between normal and cancer cells allows the nanodrug to exhibit selective lethality.Meanwhile,the depletion of GSH inhibited the expression of lipid peroxidase（GPX4）to a certain extent,thus weakening the repairing effect of GPX4 on lipid peroxidation generated during PDT,causing the cells to die in ferroptosis manner and achieving efficient synergistic treatment of MCF-7 breast cancer.Ⅲ.Boronic ester-linked porphyrin-based COF was synthesized for the specific delivery of the GPX4 inhibitor ML162 under solvothermal conditions.The borate ester bond serves as a responsive active site for endogenous overexpression of ATP in the tumor microenvironment（TME）.Porphyrins in the COF framework under NIR light irradiation can generate large amounts of reactive oxygen species,disrupting intracellular redox homeostasis and causing lipid peroxidation.With the overexpression of ATP in TME,the specific release of ML162 at the tumor site can be achieved.The released ML162 inhibited the expression of GPX4 in the cells and prevented the lipid peroxidation generated by GPX4 during PDT,which eventually led to cell death in the ferroptosis pathway,achieving efficient inhibition of HCT-116 in colon cancer cells.Ⅳ.Disulfide bonds were introduced as active sites into the amine-bonded COF framework under solvothermal conditions for the efficient targeted delivery of the cuproptosis drug elesclomol under solvothermal conditions to achieve efficient inhibition of cancer cells by the cuproptosis mechanism.In the presence of high GSH expression in tumor cells,the active site disulfide bond was opened,elesclomol was released specifically and efficiently at the tumor.While opening the disulfide bond,GSH consumes itself and improves the sensitivity of tumor cells to elesclomol.In the presence of nanodrugs,oligomerization of the important protein dihydrolipoic acid transacetylase（DLAT）in mitochondria occurs,the mitochondrial membrane potential of cells was altered,the mitochondrial structure was disrupted,and the tricarboxylic acid cycle was disturbed leading to significant changes in tricarboxylic acid metabolites.Moreover,the cell morphology under the action of nanodrugs was changed in a way different from other common ways of death,which may be a typical cell morphological feature of cuproptosis.Cuproptosis is still in the initial stage of research and has excellent potential in cancer therapeutics.