The tumor microenvironment(TME)-activatable probes have proven effective in enhancing the signalto-background ratio(SBR)for precise fluorescence imaging in tumor diagnosis.However,many fluorophores have suboptimal emi...The tumor microenvironment(TME)-activatable probes have proven effective in enhancing the signalto-background ratio(SBR)for precise fluorescence imaging in tumor diagnosis.However,many fluorophores have suboptimal emission spectra and a short Stokes shift,which may lead to overlap with bioautofluorescence,excitation,and emission spectra,limiting their use in intraoperative guidance.Herein,aγ-glutathione(GSH)responsive near-infrared(NIR)BODIPY probe,named“Pro-Dye”was synthesized with a large Stokes shift of 91 nm.The Pro-Dye can be rapidly and specifically activated by high concentrations of GSH both in solution and inside cancer cells,while remaining inactive in normal cells(Human umbilical vein endothelial cells,HUVECs).The Pro-Dye was further encapsulated by 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol)-5000(DSPE-PEG5000)to form Pro-Dye nanoparticles(NPs),making it water-dispersible for in vivo application.In vivo fluorescence imaging demonstrated that Pro-Dye NPs can accumulate at the tumor and exhibit an improved SBR compared to the“alwayson”probe(Dye NPs).Moreover,the tumor can be precisely resected under the real-time guidance of fluorescence imaging of Pro-Dye NPs,showing a well-defined tumor margin.展开更多
Numerous efforts have been devoted to altering the dynamic covalent linkers between the drug structural units in polyprodrugs from the viewpoint of molecular structure;however,the effect of their aggregation states ha...Numerous efforts have been devoted to altering the dynamic covalent linkers between the drug structural units in polyprodrugs from the viewpoint of molecular structure;however,the effect of their aggregation states has not yet been explored.Here,the effect of aggregation states on the in vitro drug release and cytotoxicity was investigated using a pH/glutathione(GSH)co-triggered degradable doxorubicin(DOX)-based polyprodrug(PDOX)as a model,which was synthesized by the facile polymerization of a pH/GSH dual-triggered dimeric prodrug(DDOX_(ss))and 2,2-dimethoxypropane(DMP)by forming acid-labile ketal bond.Owing to the pH/GSH dual-triggered disulfide/α-amide and acid-labile ketal linkers between the DOX structural units,the resultant PDOX exhibited excellent pH/GSH co-triggered DOX release.With a similar diameter,the PDOX-NPs1 nanomedicines via fast precipitation showed faster DOX release than PDOX-NPs2 via slow self-assembly,regardless of their polymerization degree(DP).The effect of aggregation states is expected to be a secondary strategy for a more desired tumor intracellular microenvironment-responsive drug delivery for tumor chemotherapy,in addition to the molecular structures of polyprodrugs as drug self-delivery systems(DSDSs).展开更多
The complexity of cancer therapy has led to the emergence of combination therapy as a promising approach to enhance treatment efficacy and safety.The integration of glutathione(GSH)-activatable two-photon photodynamic...The complexity of cancer therapy has led to the emergence of combination therapy as a promising approach to enhance treatment efficacy and safety.The integration of glutathione(GSH)-activatable two-photon photodynamic therapy(TP-PDT)and chemodynamic therapy(CDT)offers the possibility to advance precision and efficacy in anti-cancer treatments.In this study,a GSH-activatable photosensitizer(PS),namely copper-elsinochrome(CuEC),is synthesized and utilized for combination second nearinfrared(NIR-II)TP-PDT/CDT.The Cu^(2+)acts as a“lock”,suppressing the fluorescence and^(1)O_(2)generation ability of EC in a normal physiological environment(“OFF”state).However,the overexpressed GSH in the tumor microenvironment acts as the“key”,resulting in the release of EC(“ON”state)and Cu^(+)(reduced by GSH).The released EC can be utilized for fluorescence imaging and TP-PDT under NIR-II(λ=1000 nm)two-photon excitation,while Cu+can generate highly toxic hydroxyl radicals(•OH)via Fenton-like reaction for CDT.Additionally,this process consumes GSH and diminishes the tumor’s antioxidant capacity,thereby augmenting the efficacy of combination therapy.The CuEC achieves significant tumor cell ablation in both 2D monolayer cells and 3D multicellular tumor spheres through the combination of NIR-II TP-PDT and CDT.展开更多
基金supported by the Natural Science Foundation of Shaanxi Province(Nos.2023-YBSF-270,2024SF-ZDCYL-02-08)Fundamental Research Funds for the Central Universities(No.xzy022024033)+2 种基金Horizontal Project of the First Affiliated Hospital of Xi’an Jiaotong University(No.202304174)supported by the Opening Project of Structural Optimization and Application of Functional Molecules Key Laboratory of Sichuan Province(No.2023GNFZ-03)The Key Laboratory for Screening and Diagnosis of Maternal and Child Genetic Disease of Health Commission of Jiangxi Province.
文摘The tumor microenvironment(TME)-activatable probes have proven effective in enhancing the signalto-background ratio(SBR)for precise fluorescence imaging in tumor diagnosis.However,many fluorophores have suboptimal emission spectra and a short Stokes shift,which may lead to overlap with bioautofluorescence,excitation,and emission spectra,limiting their use in intraoperative guidance.Herein,aγ-glutathione(GSH)responsive near-infrared(NIR)BODIPY probe,named“Pro-Dye”was synthesized with a large Stokes shift of 91 nm.The Pro-Dye can be rapidly and specifically activated by high concentrations of GSH both in solution and inside cancer cells,while remaining inactive in normal cells(Human umbilical vein endothelial cells,HUVECs).The Pro-Dye was further encapsulated by 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol)-5000(DSPE-PEG5000)to form Pro-Dye nanoparticles(NPs),making it water-dispersible for in vivo application.In vivo fluorescence imaging demonstrated that Pro-Dye NPs can accumulate at the tumor and exhibit an improved SBR compared to the“alwayson”probe(Dye NPs).Moreover,the tumor can be precisely resected under the real-time guidance of fluorescence imaging of Pro-Dye NPs,showing a well-defined tumor margin.
文摘Numerous efforts have been devoted to altering the dynamic covalent linkers between the drug structural units in polyprodrugs from the viewpoint of molecular structure;however,the effect of their aggregation states has not yet been explored.Here,the effect of aggregation states on the in vitro drug release and cytotoxicity was investigated using a pH/glutathione(GSH)co-triggered degradable doxorubicin(DOX)-based polyprodrug(PDOX)as a model,which was synthesized by the facile polymerization of a pH/GSH dual-triggered dimeric prodrug(DDOX_(ss))and 2,2-dimethoxypropane(DMP)by forming acid-labile ketal bond.Owing to the pH/GSH dual-triggered disulfide/α-amide and acid-labile ketal linkers between the DOX structural units,the resultant PDOX exhibited excellent pH/GSH co-triggered DOX release.With a similar diameter,the PDOX-NPs1 nanomedicines via fast precipitation showed faster DOX release than PDOX-NPs2 via slow self-assembly,regardless of their polymerization degree(DP).The effect of aggregation states is expected to be a secondary strategy for a more desired tumor intracellular microenvironment-responsive drug delivery for tumor chemotherapy,in addition to the molecular structures of polyprodrugs as drug self-delivery systems(DSDSs).
基金supported by the project of the National Key Research and Development Program of China(No.2022YFA1207600)the National Natural Science Foundation of China(Nos.62005294,62375272)TIPC Director’s Fund.
文摘The complexity of cancer therapy has led to the emergence of combination therapy as a promising approach to enhance treatment efficacy and safety.The integration of glutathione(GSH)-activatable two-photon photodynamic therapy(TP-PDT)and chemodynamic therapy(CDT)offers the possibility to advance precision and efficacy in anti-cancer treatments.In this study,a GSH-activatable photosensitizer(PS),namely copper-elsinochrome(CuEC),is synthesized and utilized for combination second nearinfrared(NIR-II)TP-PDT/CDT.The Cu^(2+)acts as a“lock”,suppressing the fluorescence and^(1)O_(2)generation ability of EC in a normal physiological environment(“OFF”state).However,the overexpressed GSH in the tumor microenvironment acts as the“key”,resulting in the release of EC(“ON”state)and Cu^(+)(reduced by GSH).The released EC can be utilized for fluorescence imaging and TP-PDT under NIR-II(λ=1000 nm)two-photon excitation,while Cu+can generate highly toxic hydroxyl radicals(•OH)via Fenton-like reaction for CDT.Additionally,this process consumes GSH and diminishes the tumor’s antioxidant capacity,thereby augmenting the efficacy of combination therapy.The CuEC achieves significant tumor cell ablation in both 2D monolayer cells and 3D multicellular tumor spheres through the combination of NIR-II TP-PDT and CDT.
