Design,Synthesis And Application Of Prodrugs Tiggered By Bioorthogonal Reaction Or Glutathione

Tumors have been one of the malignant diseases that threaten all of humanity for a long time.Chemotherapy,as a routine and effective treatment,is widely used in the treatment of tumors,but chemotherapy drugs usually exhibit the reduced effectiveness of treatment and produce side effects due to their poor physical and chemical properties and lack of specificity.At present,the application of prodrug strategies is expected to tackeld this problem.Based on this,three prodrug systems were designed and synthesized to release parent drugs in response to exogenous(bioorthogonal reactions)or endogenous(overexpressed glutathione)stimuli.The prodrug systems achieved high therapeutic efficacy.The main results of this study are presented as follows:1)A two-component prodrug system was designed and synthesized based on bioorthogonal reaction.The system is mainly divided into two components,which are CPT(camptothecin)caged with vinyl ether and tetrazine derivatives linked by near-infrared dyes.The bioorthogonal reaction between the two components in an aqueous media generated strong fluorescence and released the active drug.Moreover,the molecular prodrug and trigger were then encapsulated in phospholipid liposomes to afford the nanosized liposomal bioorthogonal system.The prepared liposome bioorthogonal system showed high cytotoxicity in tumor cells,and also exhibited highly effective tumor suppressing effects in xenograft mouse models.2)A combined therapeutic system of drug activation based on bioorthogonal reaction and photothermal therapy based on gold nanorods was designed and fabricated for tumor inhibition.The system is mainly divided into two components,namely vinyl ether caged CPT(camptothecin)and gold nanorods immobilized with PEGylated tetrazine.The tetrazine-based trigger effectively mediates the bioorthogonal reaction and the release of camptothecin for chemotherapy,and the gold nanorods exhibits high photothermal capability for photothermal therapy and three-dimensional optoacoustic imaging.and ultimately achieve collaborative treatment.The system showed enhanced cytotoxicity to tumor cells,and in vivo experiments,the combined effect of chemotherapy and photothermal therapy in the system greatly inhibited the growth of tumors in mice.3)A nanoprodrug system based on glutathione response and fluorescence/photoacoustic dual imaging was designed and synthesized for the treatment of in situ non-small cell lung cancer.A tyrosine kinase inhibitor gefitinib and a NIR chromophore was covalently linked to the cleavable disulfide bond via carbonate bond to the main molecule of nano-prodrug,and the main molecule could self-assemble into nanoparticles in an aqueous media.In the process of forming nanoparticles,celastrol,an Akt inhibitor,was encapsulated to form nano-prodrug CEL@G-SS-NIR for the treatment of in situ lung cancer.The nano-prodrug could release two anti-cancer drugs and near-infrared chromophores in response to the over-expressed glutathione in tumor cells.The released two anticancer drugs can achieve synergistic treatment by inhibiting the upstream and downstream signaling of the EGFR signaling pathway,respectively,while the released NIR chromophore can realize fluorescence and photoacoustic imaging of drug release behavior.A mouse model of in situ non-small cell lung cancer was established,and treated with nano-prodrug CEL@G-SS-NIR.The results showed that the nano-prodrug system exhibits significant therapeutic effect.