Metal-organic frameworks(MOFs)combined with specific ligands are highly adaptable smart materials that can respond to external and physiological stimuli.In this study,we introduced a pyridinyl zwitterionic ligand with...Metal-organic frameworks(MOFs)combined with specific ligands are highly adaptable smart materials that can respond to external and physiological stimuli.In this study,we introduced a pyridinyl zwitterionic ligand with light/pH dual response into magnetic MOF composite(Fe_(3)O_(4)@ZW-MOF)for enrichment of phosphorylated peptides for the first time.The introduction of the developed ligand gives MOF material dual response properties.Light stimulation affects the generation/disappearance of free radicals of the pyridine derivative,resulting in a change in the charge gradient of the zwitterion,and zwitterion can also regulate the p H of the solution by adding acid or base.Therefore,the reversible capture and release of phosphorylated peptides can be easily achieved by adjusting light and pH.The established phosphorylated peptide enrichment platform exhibits high sensitivity(detection limit of 1 fmol),high selectivity(β-casein:BSA,1:1000),and good reusability(7 cycles).In addition,the method was applied to the enrichment of phosphorylated peptides in complex systems(non-fat milk and human serum),demonstrating the feasibility of this method for phosphoproteom analysis.In conclusion,the synthesized Fe_(3)O_(4)@ZW-MOF is a promising MOF material,which provides the possibility to advance the application of responsive MOFs materials in proteomics.展开更多
Stimuli-triggered release and alleviating resistance of iridium(Ⅲ)-based drugs at tumor sites remains challengeable for clinical hepatoma therapy.Herein,a doxorubicin@iridium-transferrin(DOX@Ir-TF)nanovesicle was syn...Stimuli-triggered release and alleviating resistance of iridium(Ⅲ)-based drugs at tumor sites remains challengeable for clinical hepatoma therapy.Herein,a doxorubicin@iridium-transferrin(DOX@Ir-TF)nanovesicle was synthesized by carboxylated-transferrin(TF)and doxorubicin-loaded amphiphilic iridium-amino with quaternary ammonium(QA)groups and disulfide bonds.The QA groups enhanced photophysical properties and broadened production capacity of photoinduced-reactive oxygen species(ROS),while the disulfide-bridged bonds regulated oxidative stress levels through reacting with glutathione(GSH);simultaneously,modification of TF improved recognition and endocytosis of the nanovesicle for tumor cells.Based on in-vitro results,a controlled-release behavior of DOX upon a dualresponsiveness of GSH and near-infrared ray(NIR)irradiation was presented,along with high-efficiency generation of ROS.After an intravenous injection,the nanovesicle was targeted at tumor sites,realizing TF-navigated photoacoustic imaging guidance and synergistic chemotherapy-photodynamic therapy under NIR/GSH stimulations.Overall,newly-synthesized DOX@Ir-TF nanovesicle provided a potential in subcutaneous hepatocellular carcinoma therapy due to integrations of targeting delivery,dual-stimuli responsive release,synergistic therapy strategy,and real-time monitoring.展开更多
Development of sensitive biosensors for biocatalytic transformations monitoring is in high demand but remains a great challenge. It is ascribed to the current strategies that focused on the single metabolite detection...Development of sensitive biosensors for biocatalytic transformations monitoring is in high demand but remains a great challenge. It is ascribed to the current strategies that focused on the single metabolite detection, which may bring about the relatively low sensitivity and false diagnosis result. Herein, we report the design and fabrication of novel carbon dots(CDs) with strong orange light emission, pH and H2O2 dual-responsive characteristics. The fluorescence quenching of CDs by H+and H2O2 enables the highly sensitive detection of H+/H2O2-generating biocatalytic transformations. This is exemplified by the glucose oxidase-mediated catalytic oxidation reaction on glucose, in which H+and H2O2 would be formed. As compared to the case in which glucose is present, significant fluorescence reduction is detected, and the fluorescence intensity is negatively proportional to glucose concentration. Thus, highly sensitive detection of glucose was readily achieved with a detection limit down to 10.18 nmol/L. The prepared CDs not only realize the highly sensitive detection of glucose, but also allows the probing other substances by changing the enzymes, thus providing a versatile platform, and demonstrating good potential to be used for biocatalytic transformations effective monitoring.展开更多
Nanomedicine has revolutionized disease theranostics by the accurate diagnosis and efficient therapy.Here,the PAMAM dendrimer decorated PVCL-GMA nanogels(NGs)were developed for favorable biodistribution in vivo and en...Nanomedicine has revolutionized disease theranostics by the accurate diagnosis and efficient therapy.Here,the PAMAM dendrimer decorated PVCL-GMA nanogels(NGs)were developed for favorable biodistribution in vivo and enhanced antitumor efficacy of ovarian carcinoma.By an ingenious design,the NGs with a unique structure that GMA-rich domains were localized on the surface were synthesized via precipitation polymerization.After G2 dendrimer decoration,the overall charge is changed from neutral to positive,and the NGs-G2 display the whole charge nature of positively charged corona and neutral core.Importantly,the unique architecture and charge conversion of NGs-G2 have a profound impact on the biodistribution and drug delivery in vivo.As a consequence of this alteration,the NGs-G2 as nanocarriers emerge the highly sought biodistribution of reduced liver accumulation,enhanced tumor uptake,and promoted drug release,resulting in the significantly augmented antitumor efficacy with low side effects.Remarkably,this finding is contrary to some reported work that the nanocarriers with positive charge have preferential liver uptake.Moreover,the NGs-G2 also displayed thermal/pH dual-responsive behaviors,excellent biocompatibility,improved cellular uptake,and stimuli-responsive drug release.Encouragingly,this work demonstrates a novel insight into the strategy for optimizing design,improving biodistribution and enhancing theranostic efficacy of nanocarriers.展开更多
Although sonodynamic therapy(SDT)is a promising non-invasive tumor treatment strategy due to its safety,tissue penetration depth and low cost,the hypoxic tumor microenvironment limits its therapeutic effects.Herein,we...Although sonodynamic therapy(SDT)is a promising non-invasive tumor treatment strategy due to its safety,tissue penetration depth and low cost,the hypoxic tumor microenvironment limits its therapeutic effects.Herein,we have designed and developed an oxygen-independent,ROS-amplifying chemo-sonodynamic antitumor therapy based on novel pH/GSH/ROS triple-responsive PEG-PPMDT nanoparticles.The formulated artemether(ART)/Fe_(3)O_(4)-loaded PEG-PPMDT NPs can rapidly release drug under the synergistic effect of acidic endoplasmic pH and high intracellular GSH/ROS levels to inhibit cancer cell growth.Besides,the ROS level in the NPs-treated tumor cells is magnified by ART via interactions with both Fe^(2+)ions formed in situ at acidic pH and external ultrasound irradiation,which is not affected by hypoxia tumor microenvironment.Consequently,the enriched intracellular ROS level can cause direct necrosis of ROS-stressed tumor cells and further accelerate the drug release from the ROS-responsive PEG-PPMDT NPs,achieving an incredible antitumor potency.Specifically,upon the chemo-sonodynamic therapy by ART/Fe_(3)O_(4)-loaded PEG-PPMDT NPs,all xenotransplants of human hepatocellular carcinoma(HepG2)in nude mice shrank significantly,and 40% of the tumors were completely eliminated.Importantly,the Fe3O4 encapsulated in the NPs is an efficient MRI contrast agent and can be used to guide the therapeutic procedures.Further,biosafety analyses show that the PEG-PPMDT NPs possess minimal toxicity to main organs.Thus,our combined chemo-sonodynamic therapeutic method is promising for potent antitumor treatment by controlled release of drug and facile exogenous generation of abundant ROS at target tumor sites.展开更多
Cisplatin is broad-spectrum chemotherapeutic agent that has been widely used for the treatment of a variety of malignant tumors including breast cancer.However,the cisplatin chemoresistance,which derives from the inac...Cisplatin is broad-spectrum chemotherapeutic agent that has been widely used for the treatment of a variety of malignant tumors including breast cancer.However,the cisplatin chemoresistance,which derives from the inactivation by glutathione(GSH)depletion,remains a scientific issue to solve.Here,we report a novel type of smart disulfide switchable nanoparticles complexing cisplatin(switch NPs-cisplatin)that is rationally designed,and engineered by synthesizing a hyaluronic acid disulfide bonded polyaspartic acid(HA-ss-Pasp)and complexing cisplatin.The results showed that the switch NPs-cisplatin had a nanoscale of particle size(150 nm),higher drug encapsulation efficiency(>90%),and suitable drug release profile.They demonstrated evident pH responsiveness and GSH responsiveness,and targeting effect in the resistant breast cancer cells.Furthermore,they were able to block the cisplatin depletion by GSH in the resistant cancer cells,thereby circumventing the chemoresistance.Consequently,switch NPs-cisplatin displayed a remarkable killing effect in the resistant breast cancer cells in vitro,and in the resistant breast cancer-bearing mice.In conclusion,switch NPs-cisplatin could be used as a smart formulation of cisplatin for overcoming the chemoresistance of breast cancer.The present study also offers a universal drug delivery carrier platform for highly efficient but low systemic toxic chemotherapy.展开更多
基金the financial support of the Fundamental Research Funds for the Central Universities,JLU,ChinaOpen Project of State Key Laboratory of Supramolecular Structure and Materials,Jilin University,China(No.sklssm2022012)。
文摘Metal-organic frameworks(MOFs)combined with specific ligands are highly adaptable smart materials that can respond to external and physiological stimuli.In this study,we introduced a pyridinyl zwitterionic ligand with light/pH dual response into magnetic MOF composite(Fe_(3)O_(4)@ZW-MOF)for enrichment of phosphorylated peptides for the first time.The introduction of the developed ligand gives MOF material dual response properties.Light stimulation affects the generation/disappearance of free radicals of the pyridine derivative,resulting in a change in the charge gradient of the zwitterion,and zwitterion can also regulate the p H of the solution by adding acid or base.Therefore,the reversible capture and release of phosphorylated peptides can be easily achieved by adjusting light and pH.The established phosphorylated peptide enrichment platform exhibits high sensitivity(detection limit of 1 fmol),high selectivity(β-casein:BSA,1:1000),and good reusability(7 cycles).In addition,the method was applied to the enrichment of phosphorylated peptides in complex systems(non-fat milk and human serum),demonstrating the feasibility of this method for phosphoproteom analysis.In conclusion,the synthesized Fe_(3)O_(4)@ZW-MOF is a promising MOF material,which provides the possibility to advance the application of responsive MOFs materials in proteomics.
基金supported by the National Key R&D Program of China(Nos.2022YFB3808000,2022YFB3808001)the Project for High-Level Talent Innovation and Entrepreneurship of Quanzhou(No.2022C016R)+1 种基金the Medical Innovation Project of Science and Technology Program of Fujian Provincial Health Commission(No.2021CXA006)the Key Program of Qingyuan Innovation Laboratory(No.00221002).
文摘Stimuli-triggered release and alleviating resistance of iridium(Ⅲ)-based drugs at tumor sites remains challengeable for clinical hepatoma therapy.Herein,a doxorubicin@iridium-transferrin(DOX@Ir-TF)nanovesicle was synthesized by carboxylated-transferrin(TF)and doxorubicin-loaded amphiphilic iridium-amino with quaternary ammonium(QA)groups and disulfide bonds.The QA groups enhanced photophysical properties and broadened production capacity of photoinduced-reactive oxygen species(ROS),while the disulfide-bridged bonds regulated oxidative stress levels through reacting with glutathione(GSH);simultaneously,modification of TF improved recognition and endocytosis of the nanovesicle for tumor cells.Based on in-vitro results,a controlled-release behavior of DOX upon a dualresponsiveness of GSH and near-infrared ray(NIR)irradiation was presented,along with high-efficiency generation of ROS.After an intravenous injection,the nanovesicle was targeted at tumor sites,realizing TF-navigated photoacoustic imaging guidance and synergistic chemotherapy-photodynamic therapy under NIR/GSH stimulations.Overall,newly-synthesized DOX@Ir-TF nanovesicle provided a potential in subcutaneous hepatocellular carcinoma therapy due to integrations of targeting delivery,dual-stimuli responsive release,synergistic therapy strategy,and real-time monitoring.
基金funded by the National Natural Science Foundation of China (Nos. 21605093, 21775082 and 21575074)the Special Foundation for Distinguished Taishan Scholar of Shandong Province (No. ts201511052)
文摘Development of sensitive biosensors for biocatalytic transformations monitoring is in high demand but remains a great challenge. It is ascribed to the current strategies that focused on the single metabolite detection, which may bring about the relatively low sensitivity and false diagnosis result. Herein, we report the design and fabrication of novel carbon dots(CDs) with strong orange light emission, pH and H2O2 dual-responsive characteristics. The fluorescence quenching of CDs by H+and H2O2 enables the highly sensitive detection of H+/H2O2-generating biocatalytic transformations. This is exemplified by the glucose oxidase-mediated catalytic oxidation reaction on glucose, in which H+and H2O2 would be formed. As compared to the case in which glucose is present, significant fluorescence reduction is detected, and the fluorescence intensity is negatively proportional to glucose concentration. Thus, highly sensitive detection of glucose was readily achieved with a detection limit down to 10.18 nmol/L. The prepared CDs not only realize the highly sensitive detection of glucose, but also allows the probing other substances by changing the enzymes, thus providing a versatile platform, and demonstrating good potential to be used for biocatalytic transformations effective monitoring.
基金This research was financially supported by the Sino-German Center for Research Promotion(GZ1505),DFG(SFB 985,Functional Microgels and Microgel Systems),National Natural Science Foundation of China(81801704 and 81761148028)Science and Technology Commission of Shanghai Municipality(18520750400)Shanghai Sailing Program(18YF1415300)。
文摘Nanomedicine has revolutionized disease theranostics by the accurate diagnosis and efficient therapy.Here,the PAMAM dendrimer decorated PVCL-GMA nanogels(NGs)were developed for favorable biodistribution in vivo and enhanced antitumor efficacy of ovarian carcinoma.By an ingenious design,the NGs with a unique structure that GMA-rich domains were localized on the surface were synthesized via precipitation polymerization.After G2 dendrimer decoration,the overall charge is changed from neutral to positive,and the NGs-G2 display the whole charge nature of positively charged corona and neutral core.Importantly,the unique architecture and charge conversion of NGs-G2 have a profound impact on the biodistribution and drug delivery in vivo.As a consequence of this alteration,the NGs-G2 as nanocarriers emerge the highly sought biodistribution of reduced liver accumulation,enhanced tumor uptake,and promoted drug release,resulting in the significantly augmented antitumor efficacy with low side effects.Remarkably,this finding is contrary to some reported work that the nanocarriers with positive charge have preferential liver uptake.Moreover,the NGs-G2 also displayed thermal/pH dual-responsive behaviors,excellent biocompatibility,improved cellular uptake,and stimuli-responsive drug release.Encouragingly,this work demonstrates a novel insight into the strategy for optimizing design,improving biodistribution and enhancing theranostic efficacy of nanocarriers.
基金supported by the National Natural Science Foundation of China(51773231)the Natural Science Foundation of Guangdong Province(2016A030313315)+1 种基金Shenzhen Science and Technology Project(JCYJ20190807160801664)the Project of Key Laboratory of Sensing Technology and Biomedical Instruments of Guangdong Province(2011A060901013)。
文摘Although sonodynamic therapy(SDT)is a promising non-invasive tumor treatment strategy due to its safety,tissue penetration depth and low cost,the hypoxic tumor microenvironment limits its therapeutic effects.Herein,we have designed and developed an oxygen-independent,ROS-amplifying chemo-sonodynamic antitumor therapy based on novel pH/GSH/ROS triple-responsive PEG-PPMDT nanoparticles.The formulated artemether(ART)/Fe_(3)O_(4)-loaded PEG-PPMDT NPs can rapidly release drug under the synergistic effect of acidic endoplasmic pH and high intracellular GSH/ROS levels to inhibit cancer cell growth.Besides,the ROS level in the NPs-treated tumor cells is magnified by ART via interactions with both Fe^(2+)ions formed in situ at acidic pH and external ultrasound irradiation,which is not affected by hypoxia tumor microenvironment.Consequently,the enriched intracellular ROS level can cause direct necrosis of ROS-stressed tumor cells and further accelerate the drug release from the ROS-responsive PEG-PPMDT NPs,achieving an incredible antitumor potency.Specifically,upon the chemo-sonodynamic therapy by ART/Fe_(3)O_(4)-loaded PEG-PPMDT NPs,all xenotransplants of human hepatocellular carcinoma(HepG2)in nude mice shrank significantly,and 40% of the tumors were completely eliminated.Importantly,the Fe3O4 encapsulated in the NPs is an efficient MRI contrast agent and can be used to guide the therapeutic procedures.Further,biosafety analyses show that the PEG-PPMDT NPs possess minimal toxicity to main organs.Thus,our combined chemo-sonodynamic therapeutic method is promising for potent antitumor treatment by controlled release of drug and facile exogenous generation of abundant ROS at target tumor sites.
基金supported by the National Natural Science Foundation of China(Nos.81874303,82173752)。
文摘Cisplatin is broad-spectrum chemotherapeutic agent that has been widely used for the treatment of a variety of malignant tumors including breast cancer.However,the cisplatin chemoresistance,which derives from the inactivation by glutathione(GSH)depletion,remains a scientific issue to solve.Here,we report a novel type of smart disulfide switchable nanoparticles complexing cisplatin(switch NPs-cisplatin)that is rationally designed,and engineered by synthesizing a hyaluronic acid disulfide bonded polyaspartic acid(HA-ss-Pasp)and complexing cisplatin.The results showed that the switch NPs-cisplatin had a nanoscale of particle size(150 nm),higher drug encapsulation efficiency(>90%),and suitable drug release profile.They demonstrated evident pH responsiveness and GSH responsiveness,and targeting effect in the resistant breast cancer cells.Furthermore,they were able to block the cisplatin depletion by GSH in the resistant cancer cells,thereby circumventing the chemoresistance.Consequently,switch NPs-cisplatin displayed a remarkable killing effect in the resistant breast cancer cells in vitro,and in the resistant breast cancer-bearing mice.In conclusion,switch NPs-cisplatin could be used as a smart formulation of cisplatin for overcoming the chemoresistance of breast cancer.The present study also offers a universal drug delivery carrier platform for highly efficient but low systemic toxic chemotherapy.
