Ischemic stroke is an acute and serious cerebral vascular disease,which greatly affects people’s health and brings huge economic burden to society.Microglia,as important innate immune components in central nervous sy...Ischemic stroke is an acute and serious cerebral vascular disease,which greatly affects people’s health and brings huge economic burden to society.Microglia,as important innate immune components in central nervous system(CNS),are double-edged swords in the battle of nerve injury,considering their polarization between pro-inflammatory M1 or anti-inflammatory M2 phenotypes.High mobility group box 1(HMGB1)is one of the potent pro-inflammatory mediators that promotes the M1 polarization of microglia.18β-glycyrrhetinic acid(GA)is an effective intracellular inhibitor of HMGB1,but of poor water solubility and dose-dependent toxicity.To overcome the shortcomings of GA delivery and to improve the efficacy of cerebral ischemia therapy,herein,we designed reactive oxygen species(ROS)responsive polymer-drug conjugate nanoparticles(DGA)to manipulate microglia polarization by suppressing the translocation of nuclear HMGB1.DGA presented excellent therapeutic efficacy in stroke mice,as evidenced by the reduction of infarct volume,recovery of motor function,suppressed of M1 microglia activation and enhanced M2 activation,and induction of neurogenesis.Altogether,our work demonstrates a close association between HMGB1 and microglia polarization,suggesting potential strategies for coping with inflammatory microglia-related diseases.展开更多
Two kinds of paclitaxel（PTX） conjugate micelles,of which one contained 25%（mass fraction） PTX [M（PTX）] and the other contained 22.5%（mass fraction） of PTX and 1.4%（mass fraction） of folate（FA）[FA-M（PTX）]...Two kinds of paclitaxel（PTX） conjugate micelles,of which one contained 25%（mass fraction） PTX [M（PTX）] and the other contained 22.5%（mass fraction） of PTX and 1.4%（mass fraction） of folate（FA）[FA-M（PTX）],were prepared for cell apoptosis and anti-tumor activity evaluation on U14 cervical cancer mouse models in comparison with 0.9%（mass fraction） saline（control） and equivalent Taxol.Seven days after tail intravenous injection of the drugs,the mice were sacrificed to measure the tumor masses.The average tumor masses were 4.26,2.89,2.63,and 2.17 g for the control,Taxol,M（PTX） and FA-M（PTX） groups,respectively.The inhibition rates of tumor growth calculated for the three drug groups were 32%,38% and 49%,respectively.Flow cytometry（FC） analysis and terminal deoxynucleotidyl transferase（TdT）-mediated deoxyuridine triphosphate（dUTP） nick end labeling（TUNEL） assay were conducted on the cancer tissues.The cell apoptosis rates based on the FC data and the TUNEL data were 20%,31%,37%,42%,and 10%,22%,26%,34%,respectively,both showing statistically significant differences（P〈0.05） between three drug groups and the control group,and between the FA-M（PTX） group and the other two drug groups.In conclusion,the composite FA-M（PTX） micelles can be used for U14 cervical cancer treatment.展开更多
Cell transplantation has been proved the promising therapeutic effects on intervertebral disc degeneration(IVDD).However,the increased levels of reactive oxygen species(ROS)in the degenerated region will impede the ef...Cell transplantation has been proved the promising therapeutic effects on intervertebral disc degeneration(IVDD).However,the increased levels of reactive oxygen species(ROS)in the degenerated region will impede the efficiency of human adipose-derived stem cells(human ADSCs)transplantation therapy.It inhibits human ADSCs proliferation,and increases human ADSCs apoptosis.Herein,we firstly devised a novel amphiphilic copolymer PEG-PAPO,which could self-assemble into a nanosized micelle and load lipophilic kartogenin(KGN),as a single complex(PAKM).It was an injectable esterase-responsive micelle,and showed controlled release ability of KGN and apocynin(APO).Oxidative stimulation promoted the esterase activity in human ADSCs,which accelerate degradation of esterase-responsive micelle.Compared its monomer,the PAKM micelle possessed better bioactivities,which were attributed to their synergistic effect.It enhanced the viability,autophagic activation(P62,LC3 II),ECM-related transcription factor(SOX9),and ECM(Collagen II,Aggrecan)maintenance in human ADSCs.Furthermore,it is demonstrated that the injection of PAKM with human ADSCs yielded higher disc height and water content in rats.Therefore,PAKM micelles perform promoting cell survival and differentiation effects,and may be a potential therapeutic agent for IVDD.展开更多
Multi-functional mikto-arm star polymers containing three different arms [hydrophilic, SN-38-P（OEGMAs_9）11, cationizable, SN-38-P（DMAEMA）3s and hydrophobic, SN-38-P（BMA）26] were prepared by RAFT polymerization v...Multi-functional mikto-arm star polymers containing three different arms [hydrophilic, SN-38-P（OEGMAs_9）11, cationizable, SN-38-P（DMAEMA）3s and hydrophobic, SN-38-P（BMA）26] were prepared by RAFT polymerization via an arm-first approach using a cleavable cross-linker. The star polymers were cleaved to the linear arms with tributylphosphine as a reducing agent. The decrease in molecular weight observed is consistent with the initial stars having approximately five arms, Blue fluorescence was observed when a solution of mikto-arm star was irradiated under a 365 nm light proving the retention of the SN-38 moiety during star formation by RAFT polymerization. Thus these polymer-drug conjugates can be considered as potential delivery vehicles for cancer therapy. The P（DMAEMA） arms can be quaternized using iodomethane, allowing star polymers to bind negatively charged small interfering RNA （siRNA） and potentially be used as a carrier for that material.展开更多
In the present study, we designed and fabricated pH-sensitive polymeric micelles based on the conjugate of poly（2-ethyl-2-oxazoline）-poly（D,L-lactide）（PEOz-PLA） with doxorubicin（PEOz-PLA-imi-DOX） to efficientl...In the present study, we designed and fabricated pH-sensitive polymeric micelles based on the conjugate of poly（2-ethyl-2-oxazoline）-poly（D,L-lactide）（PEOz-PLA） with doxorubicin（PEOz-PLA-imi-DOX） to efficiently inhibit tumor cell growth. Hence, PEOz-PLA-imi-DOX was successfully synthesized by connecting DOX to the hydrophobic end of pH-sensitive PEOz-PLA via acid cleavable benzoic imine linker and characterized by 1 H NMR spectrum and thin layer chromatography. The critical micelle concentration of PEOz-PLA-imi-DOX was determined to be（14.84±3.85） mg/L. The conjugate micelles（denoted as PP-DOX-PM） formed by PEOz-PLA-imi-DOX using film-hydration method were characterized to have a nano-scaled size of about 21 nm in diameter, and the drug loading content was 1.67%. PP-DOX-PM showed pH-dependent drug release behavior with gradually accelerated release of DOX with decrease of pH value, illustrating the micelles＇ distinguishing feature of endo/lysosomal pH from physiological pH by accelerating drug release. As anticipated, PP-DOX-PM maintained the cytotoxicity of DOX against MDA-MB-231 cells. Collectively, PP-DOX-PM might have great potential for effective suppression of tumor growth.展开更多
基金support of the National Natural Science Foundation of China(No.22161132027,51822306)Key Research and Development Program of Zhejiang Province(No.2020C03042)the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study(SN-ZJU-SIAS-006).
文摘Ischemic stroke is an acute and serious cerebral vascular disease,which greatly affects people’s health and brings huge economic burden to society.Microglia,as important innate immune components in central nervous system(CNS),are double-edged swords in the battle of nerve injury,considering their polarization between pro-inflammatory M1 or anti-inflammatory M2 phenotypes.High mobility group box 1(HMGB1)is one of the potent pro-inflammatory mediators that promotes the M1 polarization of microglia.18β-glycyrrhetinic acid(GA)is an effective intracellular inhibitor of HMGB1,but of poor water solubility and dose-dependent toxicity.To overcome the shortcomings of GA delivery and to improve the efficacy of cerebral ischemia therapy,herein,we designed reactive oxygen species(ROS)responsive polymer-drug conjugate nanoparticles(DGA)to manipulate microglia polarization by suppressing the translocation of nuclear HMGB1.DGA presented excellent therapeutic efficacy in stroke mice,as evidenced by the reduction of infarct volume,recovery of motor function,suppressed of M1 microglia activation and enhanced M2 activation,and induction of neurogenesis.Altogether,our work demonstrates a close association between HMGB1 and microglia polarization,suggesting potential strategies for coping with inflammatory microglia-related diseases.
基金Supported by the National Natural Science Foundation of China(Nos.20674084,21004062,51103148)the National Basic Research Program of China(No.2009CB930102)the National High-Tech Research and Development Program of China(No.2007AA03Z535)
文摘Two kinds of paclitaxel（PTX） conjugate micelles,of which one contained 25%（mass fraction） PTX [M（PTX）] and the other contained 22.5%（mass fraction） of PTX and 1.4%（mass fraction） of folate（FA）[FA-M（PTX）],were prepared for cell apoptosis and anti-tumor activity evaluation on U14 cervical cancer mouse models in comparison with 0.9%（mass fraction） saline（control） and equivalent Taxol.Seven days after tail intravenous injection of the drugs,the mice were sacrificed to measure the tumor masses.The average tumor masses were 4.26,2.89,2.63,and 2.17 g for the control,Taxol,M（PTX） and FA-M（PTX） groups,respectively.The inhibition rates of tumor growth calculated for the three drug groups were 32%,38% and 49%,respectively.Flow cytometry（FC） analysis and terminal deoxynucleotidyl transferase（TdT）-mediated deoxyuridine triphosphate（dUTP） nick end labeling（TUNEL） assay were conducted on the cancer tissues.The cell apoptosis rates based on the FC data and the TUNEL data were 20%,31%,37%,42%,and 10%,22%,26%,34%,respectively,both showing statistically significant differences（P〈0.05） between three drug groups and the control group,and between the FA-M（PTX） group and the other two drug groups.In conclusion,the composite FA-M（PTX） micelles can be used for U14 cervical cancer treatment.
基金This study was supported by grants from the Nature Science Foundation of Zhejiang Province(Y20H060063,LY19H060005,LQ18H060003,LR18E030002,LY18H060004)the Medical and Health Innovation Talent Support Program of Zhejiang Province(2020RC011)+5 种基金the National Natural Science Foundation of China(NO.82072465,NO.81772379,NO.81972096,NO.81902238,NO.21774109,NO.51973188,NO.51522304)the Health Foundation of Zhejiang Province(2018KY092,WKJ-ZJ-1903)the China Postdoctoral Science Foundation(2017M612011)the Zhejiang University Education Foundation Global Partnership Fund,a project supported by the Scientific Research Fund of Zhejiang Provincial Education Department(Y201941476 and Y201941491)Zhejiang Undergraduate Talent Project(grant no.2020R401212)the Scientific Research Fund of Zhejiang Provincial Education Department(Y201941476).
文摘Cell transplantation has been proved the promising therapeutic effects on intervertebral disc degeneration(IVDD).However,the increased levels of reactive oxygen species(ROS)in the degenerated region will impede the efficiency of human adipose-derived stem cells(human ADSCs)transplantation therapy.It inhibits human ADSCs proliferation,and increases human ADSCs apoptosis.Herein,we firstly devised a novel amphiphilic copolymer PEG-PAPO,which could self-assemble into a nanosized micelle and load lipophilic kartogenin(KGN),as a single complex(PAKM).It was an injectable esterase-responsive micelle,and showed controlled release ability of KGN and apocynin(APO).Oxidative stimulation promoted the esterase activity in human ADSCs,which accelerate degradation of esterase-responsive micelle.Compared its monomer,the PAKM micelle possessed better bioactivities,which were attributed to their synergistic effect.It enhanced the viability,autophagic activation(P62,LC3 II),ECM-related transcription factor(SOX9),and ECM(Collagen II,Aggrecan)maintenance in human ADSCs.Furthermore,it is demonstrated that the injection of PAKM with human ADSCs yielded higher disc height and water content in rats.Therefore,PAKM micelles perform promoting cell survival and differentiation effects,and may be a potential therapeutic agent for IVDD.
基金the China Scholarship Council for partial financial support
文摘Multi-functional mikto-arm star polymers containing three different arms [hydrophilic, SN-38-P（OEGMAs_9）11, cationizable, SN-38-P（DMAEMA）3s and hydrophobic, SN-38-P（BMA）26] were prepared by RAFT polymerization via an arm-first approach using a cleavable cross-linker. The star polymers were cleaved to the linear arms with tributylphosphine as a reducing agent. The decrease in molecular weight observed is consistent with the initial stars having approximately five arms, Blue fluorescence was observed when a solution of mikto-arm star was irradiated under a 365 nm light proving the retention of the SN-38 moiety during star formation by RAFT polymerization. Thus these polymer-drug conjugates can be considered as potential delivery vehicles for cancer therapy. The P（DMAEMA） arms can be quaternized using iodomethane, allowing star polymers to bind negatively charged small interfering RNA （siRNA） and potentially be used as a carrier for that material.
基金National Natural Science Foundation of China(Grant No.81673366)the National Key Science Research Program of China(973 Program,Grant No.2015CB932100)
文摘In the present study, we designed and fabricated pH-sensitive polymeric micelles based on the conjugate of poly（2-ethyl-2-oxazoline）-poly（D,L-lactide）（PEOz-PLA） with doxorubicin（PEOz-PLA-imi-DOX） to efficiently inhibit tumor cell growth. Hence, PEOz-PLA-imi-DOX was successfully synthesized by connecting DOX to the hydrophobic end of pH-sensitive PEOz-PLA via acid cleavable benzoic imine linker and characterized by 1 H NMR spectrum and thin layer chromatography. The critical micelle concentration of PEOz-PLA-imi-DOX was determined to be（14.84±3.85） mg/L. The conjugate micelles（denoted as PP-DOX-PM） formed by PEOz-PLA-imi-DOX using film-hydration method were characterized to have a nano-scaled size of about 21 nm in diameter, and the drug loading content was 1.67%. PP-DOX-PM showed pH-dependent drug release behavior with gradually accelerated release of DOX with decrease of pH value, illustrating the micelles＇ distinguishing feature of endo/lysosomal pH from physiological pH by accelerating drug release. As anticipated, PP-DOX-PM maintained the cytotoxicity of DOX against MDA-MB-231 cells. Collectively, PP-DOX-PM might have great potential for effective suppression of tumor growth.
