Synthesis And Anti-tumor Activity Of Cyclopeptide Fenestin A Derivative And Nanomaterial FA-CDs/Cu/Fc@3BP

Cancer is a serious threat to human health,and traditional cancer treatment strategies are plagued by problems such as metastasis and recurrence,multidrug resistance,tumour heterogeneity and immune escape,prompting the search for therapeutic agents and treatments with greater efficacy.Harnessing the rich sources and chemical diversity of natural products to develop promising new drugs for cancer control is one way to improve the efficacy of cancer treatment.Peptides,which play an important role in human physiology,have received increasing attention in recent years and a large number of peptides have been used as clinical therapeutic agents.The main features of the tumour microenvironment（TME）also provide many ideas for selective and efficient treatment of tumours.Various strategies to modulate the TME,such as increasing oxygen levels,disrupting redox homeostasis and modulating tumour immunosuppression,have been proposed to enhance the effectiveness of cancer treatment.In recent years,specific treatment modalities such as chemodynamic therapy（CDT）,photothermal therapy（PTT）,photodynamic therapy（PDT）and immunotherapy have also been developed.In particular,with the development of nanoscience,targeted-mediated therapy,bioimaging-mediated therapy and multimodal synergistic therapy have shown great promise,bringing new hope for cancer treatment.The research in this thesis is divided into the following two aspects:1.Synthesis and antitumor activity of cyclic peptide Fenestin A derivativesThe cyclic tetrapeptide cyclo-（Pro-Pro-Leu-Ile）（Fenestin A）is a natural product isolated from the sponge Leucophloeus fenestrata with four S-amino acids in the ring and little anti-tumour activity.Various cyclic peptide analogs of Fenestin A were synthesised by intramolecular photoinduced single electron transfer cyclization reactions.The incorporation of thiazole and rigid isoindolinone fragments was found to improve the bioactivity of the cyclopeptide.Detailed in vitro studies of the apoptosis mechanism,mitochondrial membrane potential,cell cycle,intracellular Ca²⁺concentration,and lactate dehydrogenase activity following treatment with a cyclopeptide showed that the cyclopeptide could induce apoptosis of tumor cells and lead to cycle arrest in the G2/M phase.The research also suggested that the photoinduced reaction could be applied to construct cyclic peptides stereoselectively,and the introduction of rigid fragments could enhance the biological activity of cyclopeptide drugs.2.Inhibition of HIF-1αexpression and antitumor activity by FA-CDs/Cu/Fc@3BP oxygenationThe FA-CDs/Cu/Fc@3BP nanoparticles were designed and prepared for synergistic enhancement of PTT/CDT and oxygenation to inhibit the expression of hypoxia-inducing factors,and the loaded cellular respiration inhibiting 3BP assisted in alleviating tumour hypoxia.FA-CDs/Cu/Fc@3BP nanoparticles retained the targeting effect of folic acid（FA）,effectively depleted GSH in tumor cells,increased ROS levels,induced massive apoptosis in cancer cells,elicited immune response,combined with immune checkpoint blockerα-PD-L1,ablated primary tumors and effectively inhibited distal tumors.