Construction Of Pillar[5]arene-based Chiral Vesicles With Metal-porphyrin Guests For Synergistic Treatment Of Tumors And Reduction Of Tumor Cisplatin Resistance

As one of the most important diseases threatening human life,the diagnosis and treatment of malignant tumors has always been an important issue for scientists.As the most commonly used first-line treatment,the therapeutic effect of chemotherapy is often limited by factors such as poor water solubility,low targeting ability,and limited stability.In addition,the toxic side effects of chemotherapy drugs and tumor resistance can also limit the effectiveness of treatment..In view of the inherent defects of traditional drug treatment,scientists have developed a variety of treatments such as photodynamic therapy（PDT）,chemodynamic therapy（CDT）and sonodynamic therapy by using the special microenvironment of tumors.Tetraphenylporphyrin（TPP）and its derivatives are a common photosensitizer（Fe TPPNHC）,which has significant near-infrared PDT efficiency while the internal cavity can carry different metal elements,so as to achieve the effect of synergistic treatment.Unfortunately,the targeting ability of TPP limits its further development and application..As an emerging supramolecular macrocycle,pillar[n]arenes have been widely studied and applied in the therapy of tumor.Carboxylated pillar[5]arene has good host-guest recognition performance and high synthesis efficiency which is easy to self-assemble into vesicles after guest identification,thus serving as a good drug delivery vehicle.However,this vesicle only has acid response to tumor cells,and how to make this vesicle have stronger biofilm response characteristics and enhance the ability to target tumors has become one of the focuses of our research.Based on the research of PDT,CDT and traditional drug treatment,as well as water-soluble pillar[5]arene drug delivery system,the main research work in this paper is divided into the following three parts:（1）Host-guest recognition of chiral glucose-modified pillar[5]arene and alkyl-Fe porphyrin derivatives and their construction of self-assembled chiral vesiclesTaking advantage of the easy modification of column aromatic hydrocarbons,a variety of host-guest complexes in response to environmental stimuli can be constructed.Carboxylated pillar[n]arenes have good acid-response performance,and chiral pillar[n]arenes can be formed after D/L-glucose modification.By modifying the alkyl long chain of tetraphenylporphyrin（TPP）,TPP had the host-guest recognition effect of the chiral pillar[5]arene,and then the interaction mode was verified by nuclear magnetism,and the guest was Fe TPPNHC and the main body was chiral pillar[5]arene by ultraviolet titration and fluorescence titration,respectively.After determining the optimal host-guest identification ratio with job’s titration,the critical micelle concentration was determined with a pyrene fluorescent probe.Finally,the morphology of LOX@LCP5（?）Fe TPPNHC vesicles was characterized by transmission electron microscopy at greater than the critical micelle concentration,which confirmed the successful construction of such vesicles and further explored the encapsulation rate and acid response performance of the drug.（2）Application of LOX@LCP5（?）Fe TPPNHC in targeted delivery of LOX and synergistic treatment of tumors and inhibition of tumor metastasisDue to the characteristics of lactic acid accumulation,H₂O₂and GSH increase in the tumor microenvironment,PDT and CDT are greatly dynamically limited.Lactate oxidase（LOX）has the effect of consuming lactic acid and thereby inhibiting tumor metastasis.Fe³⁺not only has the ability to catalyze H₂O₂oxygen production in the cytoplasm to promote PDT,but also consumes GSH to obtain Fe²⁺and enhance CDT performance.We verified the ability of supramolecular to consume GSH,the ability to catalyze the production of O₂by H₂O₂,and the ability of supramolecular vesicles to catalyze the production of lactic acid from H₂O₂,respectively,and finally characterized the photodynamic and chemical-dynamic properties by probes.In biological experiments,we verified for the first time that vesicles formed by L-type glucose-modified pillar[5]arene target tumor tissue by chiral recognition,and have been confirmed in cell experiments and in vivo experiments.（3）Construction of DDP@LCP5（?）Cu TPPBr and its application in reduction of tumor cisplatin resistanceTumor cells,like normal cells,are stressed by the tumor microenvironment during tumor production,proliferation,metastasis and immune stress,and gradually develop drug resistance in the process of continuous administration.Cisplatin（DDP）is a common inorganic chemotherapy drug whose use is limited due to its side effects and resistance during treatment.Scientists have found that drug resistance is mainly caused by reduced intake,increased elimination,and increased GSH.In the same way,we synthesized a halogenated alkyl porphyrin as a guest to assist in the transport of Cu²⁺and synergistic consumption of GSH through chemodynamic therapy means to reduce the tumor cisplatin resistance.