A new chromogenic and fluorescent ＂turn-on＂ chemodosimeter 3 was designed and synthesized by using a fluoride-sensitive self-immolative linker, in combination with the fluorescent dyes 7-hydroxy-4-trifluoromethyl co...A new chromogenic and fluorescent ＂turn-on＂ chemodosimeter 3 was designed and synthesized by using a fluoride-sensitive self-immolative linker, in combination with the fluorescent dyes 7-hydroxy-4-trifluoromethyl coumarin. The chemodosimeter exhibited high selectivity and sensitivity toward fluoride anions through ＂turn-on＂ chromogenic and fluorogenic dual modes.展开更多
Self-immolative linkers have been widely used to construct prodrugs to improve their efficacy and safety.In this study,we report the use of phenoxysilyl linker as a self-immolative unit to prepare antibody-drug conjug...Self-immolative linkers have been widely used to construct prodrugs to improve their efficacy and safety.In this study,we report the use of phenoxysilyl linker as a self-immolative unit to prepare antibody-drug conjugates(ADCs).Phenoxysily based ADC Ate-PPS-CA4 was prepared and its release was systematically investigated by mass spectrometry.Biological evaluation showed that Ate-PPS-CA4 displayed the ability to target delivery and self-immolative release the active payload CA4 on PD-L1 positive cells MDA-MB-231.As the same with its payload CA4,it could arrest the cell cycle to the G2/M phase and induced changes in cell morphology at the dose of its IC_(50).The development of this linker with novel drug release mechanisms will expand the methodology to construct ADCs,especially for non-internalizing ADCs by extracellular cleavage.展开更多
Rheumatoid arthritis(RA)is a systemic autoimmune disease that leads to the destruction of articular cartilage and bone.RA is characterized by immune cell infiltration and abnormal proliferation of synoviocytes in the ...Rheumatoid arthritis(RA)is a systemic autoimmune disease that leads to the destruction of articular cartilage and bone.RA is characterized by immune cell infiltration and abnormal proliferation of synoviocytes in the joints.Herein,we developed a biomimetic formulation via co-loading the anti-inflammatory agent Celastrol(Cel)along with the stabilizer Vitamin K(VK)in antirheumatic methotrexate(MTX)-conjugated Pluronic F127(F127)micelles.Micelles were then coated with B cell derived membrane,yielding MTX loaded Cel Micelle(CeViM)-micelle@B,which were investigated for RA treatment.VK,used at levels well within safety margins,was identified as a carrier compound that could stabilize Cel within micelles,increasing the encapsulation efficiency of Cel.In addition,MTX,a front-line RA therapeutic,was chemically grafted to F127 via a responsive linker sensitive to the chemically reducing environments.As such,CeViM-micelle@B released pristine MTX in response to the intracellular reducing environments,which combined with Cel to suppress pro-inflammatory responses.B cell membrane coating enhanced accumulation of CeViM-micelle@B in joints,leading to a 75%decrease of inflammatory cytokine secretion in vitro,and significantly ameliorated cartilage and bone structures in the collagen-induced arthritis murine model.Taken together,this biomimetic nanoparticle holds potential as a nextgeneration targeted RA treatment.展开更多
基金financial support from National Natural Science Foundation of China (No. 21202099)the Science Foundation of Shanghai Institute of Technology (No. YJ2011-75)the Opening Fund of Shanghai Key Laboratory of Chemical Biology (No. SKLCB-2014-01)
文摘A new chromogenic and fluorescent ＂turn-on＂ chemodosimeter 3 was designed and synthesized by using a fluoride-sensitive self-immolative linker, in combination with the fluorescent dyes 7-hydroxy-4-trifluoromethyl coumarin. The chemodosimeter exhibited high selectivity and sensitivity toward fluoride anions through ＂turn-on＂ chromogenic and fluorogenic dual modes.
基金supported by Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine at Shanghai Tech University。
文摘Self-immolative linkers have been widely used to construct prodrugs to improve their efficacy and safety.In this study,we report the use of phenoxysilyl linker as a self-immolative unit to prepare antibody-drug conjugates(ADCs).Phenoxysily based ADC Ate-PPS-CA4 was prepared and its release was systematically investigated by mass spectrometry.Biological evaluation showed that Ate-PPS-CA4 displayed the ability to target delivery and self-immolative release the active payload CA4 on PD-L1 positive cells MDA-MB-231.As the same with its payload CA4,it could arrest the cell cycle to the G2/M phase and induced changes in cell morphology at the dose of its IC_(50).The development of this linker with novel drug release mechanisms will expand the methodology to construct ADCs,especially for non-internalizing ADCs by extracellular cleavage.
基金This work was supported by the National Natural Science Foundation of China(22375144 and 32071384)the National Key Research and Development Program(2021YFC2102300)+1 种基金the basic research project of Shanxi Science and Technology Department(202103021224342)Key Research and Development(R&D)Projects of Shanxi Province(2021XM01).
文摘Rheumatoid arthritis(RA)is a systemic autoimmune disease that leads to the destruction of articular cartilage and bone.RA is characterized by immune cell infiltration and abnormal proliferation of synoviocytes in the joints.Herein,we developed a biomimetic formulation via co-loading the anti-inflammatory agent Celastrol(Cel)along with the stabilizer Vitamin K(VK)in antirheumatic methotrexate(MTX)-conjugated Pluronic F127(F127)micelles.Micelles were then coated with B cell derived membrane,yielding MTX loaded Cel Micelle(CeViM)-micelle@B,which were investigated for RA treatment.VK,used at levels well within safety margins,was identified as a carrier compound that could stabilize Cel within micelles,increasing the encapsulation efficiency of Cel.In addition,MTX,a front-line RA therapeutic,was chemically grafted to F127 via a responsive linker sensitive to the chemically reducing environments.As such,CeViM-micelle@B released pristine MTX in response to the intracellular reducing environments,which combined with Cel to suppress pro-inflammatory responses.B cell membrane coating enhanced accumulation of CeViM-micelle@B in joints,leading to a 75%decrease of inflammatory cytokine secretion in vitro,and significantly ameliorated cartilage and bone structures in the collagen-induced arthritis murine model.Taken together,this biomimetic nanoparticle holds potential as a nextgeneration targeted RA treatment.
