Objective:To construct a novel nanoplatform GNS@CaCO3/Ce6-NK by loading the CaCO3-coated gold nanostars(GNSs)with Chlorin e6 molecules(Ce6)into human peripheral blood mononuclear cells(PBMCs)-derived NK cells for tumo...Objective:To construct a novel nanoplatform GNS@CaCO3/Ce6-NK by loading the CaCO3-coated gold nanostars(GNSs)with Chlorin e6 molecules(Ce6)into human peripheral blood mononuclear cells(PBMCs)-derived NK cells for tumor targeted therapy.Methods:GNS@CaCO3/Ce6 nanoparticles were prepared and characterized by TEM and UV-vis.The cell surface markers and cytokines secretion of NK cells before and after loading the GNS@CaCO3/Ce6 nanoparticles were detected by Flow Cytometry(FCM)and ELISA.Effects of the GNS@CaCO3/Ce6-NK cells on A549 cancer cells was determined by FCM and CCK-8.Intracellular fluorescent signals of GNS@CaCO3/Ce6-NK cells were detected via Confocal laser scanning microscopic(CLSM)and FCM at different time points.Intracellular ROS generation of GNS@CaCO3/Ce6-NK cells under laser irradiation were examined by FCM.The distribution of GNS@CaCO3/Ce6-NK in A549 tumor-bearing mice were observed by fluorescence imaging and PA imaging.The combination therapy of GNS@CaCO3/Ce6-NK under laser irradiation were investigated on tumor-bearing mice.Results:The coated CaC03 shell on the surface of GNSs exhibited prominent delivery and protection effect of Ce6 during the cellular uptake process.The as-prepared multifunctional GNS@CaCO3/Ce6-NK cells possessed bimodal functions of fluorescence imaging and photoacoustic imaging.The as-prepared multifunctional GNS@CaCO3/Ce6-NK cells could actively target tumor tissues with the enhanced photothermal/photodynamic therapy and immunotherapy.Conclusions:The GNS@CaCO3/Ce6-NK shows effective tumor-targeting ability and prominent therapeutic efficacy toward lung cancer A549 tumor-bearing mice.Through fully utilizing the features of GNSs and NK cells,this new nanoplatform provides a new synergistic strategy for enhanced photothermal/photodynamic therapy and immunotherapy in the field of anticancer development in the near future.展开更多
Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists,which is time-consuming,high cost and waste materials.This research aims to integrate vario...Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists,which is time-consuming,high cost and waste materials.This research aims to integrate various computational tools,including machine learning,molecular dynamic simulation and physiologically based absorption modeling(PBAM),to enhance andrographolide(AG)/cyclodextrins(CDs)formulation design.The light GBM prediction model we built before was utilized to predict AG/CDs inclusion's binding free energy.AG/γ-CD inclusion complexes showed the strongest binding affinity,which was experimentally validated by the phase solubility study.The molecular dynamic simulation was used to investigate the inclusion mechanism between AG andγ-CD,which was experimentally characterized by DSC,FTIR and NMR techniques.PBAM was applied to simulate the in vivo behavior of the formulations,which were validated by cell and animal experiments.Cell experiments revealed that the presence of D-α-Tocopherol polyethylene glycol succinate(TPGS)significantly increased the intracellular uptake of AG in MDCKMDR1 cells and the absorptive transport of AG in MDCK-MDR1 monolayers.The relative bioavailability of the AG-CD-TPGS ternary system in rats was increased to 2.6-fold and 1.59-fold compared with crude AG and commercial dropping pills,respectively.In conclusion,this is the first time to integrate various computational tools to develop a new AG-CD-TPGS ternary formulation with significant improvement of aqueous solubility,dissolution rate and bioavailability.The integrated computational tool is a novel and robust methodology to facilitate pharmaceutical formulation design.展开更多
Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies,on account of its good safety and long-term memory ability.Discouragingly,low patient response rates and po...Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies,on account of its good safety and long-term memory ability.Discouragingly,low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to bedside.However,it has become evident that,although the immunosuppressive tumor microenvironment(TME)plays a pivotal role in facilitating tumor progression and metastasis,it also provides various potential targets for remodeling the immunosuppressive TME,which can consequently bolster the effectiveness of antitumor response and tumor suppression.Additionally,the particular characteristics of TME,in turn,can be exploited as avenues for designing diverse precise targeting nanomedicines.In general,it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME,thus improving the therapeutic outcomes and clinical translation prospects of immunotherapy.Herein,we will illustrate several formation mechanisms of immunosuppressive TME.More importantly,a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients'immune systems,will be reviewed.Ultimately,we will discuss the existing obstacles and future perspectives in the development of antitumor immunotherapy.Hopefully,the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.展开更多
Photodynamic therapy(PDT)is an emerging therapeutic strategy for hypertrophic scars(HS),which is heavily dependent on reactive oxygen species(ROS)generation.However,the unsatisfactory delivery and excitation of 5-amin...Photodynamic therapy(PDT)is an emerging therapeutic strategy for hypertrophic scars(HS),which is heavily dependent on reactive oxygen species(ROS)generation.However,the unsatisfactory delivery and excitation of 5-aminolevulinic acid(ALA,a commercial photosensitizer in dermatology)result in an insufficient ROS generation,and thus limit the clinical application of PDT treating HS(HS-PDT).Consequently,sophisticated transdermal co-delivery nanoethosomes(named A/A-ES)with ALA and Au nanotriangles(AuNTs)in cores are prepared via an in-situ seed-mediated growth method,and then applied to improve HS-PDT through localized surface plasmon resonance(LSPR)-enhanced ROS generation.A/A-ES display a satisfactory performance in co-delivery in HS tissue with sufficient protoporphyrin IX production and LSPR effect in cytoplasm,which is beneficial for ALA excitation as well as ROS generation.In vitrolvivo studies reveal that A/A-ES significantly improve HS-PDT in promoting to fibroblast apoptosis and collagen remodeling through LSPR-enhanced ROS generation.Therefore,this study provides a feasible strategy that integrates transdermal delivery and LSPR to enable the beneficial effects of HS-PDT through boosting the delivery and excitation of ALA.展开更多
基金supported from 973 Project (Grant No. 2015CB931802 and 2017YFA0205301)Chinese National Natural Scientific Fund (Grant No.81327002 and 81803094)+1 种基金China Postdoctoral Science Foundation (Grant No. 2017M621486)Funding from Shanghai Engineering Research Center for Intelligent diagnosis and treatment instrument (Grant No.15DZ2252000)
文摘Objective:To construct a novel nanoplatform GNS@CaCO3/Ce6-NK by loading the CaCO3-coated gold nanostars(GNSs)with Chlorin e6 molecules(Ce6)into human peripheral blood mononuclear cells(PBMCs)-derived NK cells for tumor targeted therapy.Methods:GNS@CaCO3/Ce6 nanoparticles were prepared and characterized by TEM and UV-vis.The cell surface markers and cytokines secretion of NK cells before and after loading the GNS@CaCO3/Ce6 nanoparticles were detected by Flow Cytometry(FCM)and ELISA.Effects of the GNS@CaCO3/Ce6-NK cells on A549 cancer cells was determined by FCM and CCK-8.Intracellular fluorescent signals of GNS@CaCO3/Ce6-NK cells were detected via Confocal laser scanning microscopic(CLSM)and FCM at different time points.Intracellular ROS generation of GNS@CaCO3/Ce6-NK cells under laser irradiation were examined by FCM.The distribution of GNS@CaCO3/Ce6-NK in A549 tumor-bearing mice were observed by fluorescence imaging and PA imaging.The combination therapy of GNS@CaCO3/Ce6-NK under laser irradiation were investigated on tumor-bearing mice.Results:The coated CaC03 shell on the surface of GNSs exhibited prominent delivery and protection effect of Ce6 during the cellular uptake process.The as-prepared multifunctional GNS@CaCO3/Ce6-NK cells possessed bimodal functions of fluorescence imaging and photoacoustic imaging.The as-prepared multifunctional GNS@CaCO3/Ce6-NK cells could actively target tumor tissues with the enhanced photothermal/photodynamic therapy and immunotherapy.Conclusions:The GNS@CaCO3/Ce6-NK shows effective tumor-targeting ability and prominent therapeutic efficacy toward lung cancer A549 tumor-bearing mice.Through fully utilizing the features of GNSs and NK cells,this new nanoplatform provides a new synergistic strategy for enhanced photothermal/photodynamic therapy and immunotherapy in the field of anticancer development in the near future.
基金financially supported by the FDCT Project 0029/2018/A1the University of Macao Research Grants(MYRG2019-00041-ICMS)performed in part at the High-Performance Computing Cluster(HPCC)which is supported by Information and Communication Technology Office(ICTO)of the University of Macao。
文摘Current formulation development strongly relies on trial-and-error experiments in the laboratory by pharmaceutical scientists,which is time-consuming,high cost and waste materials.This research aims to integrate various computational tools,including machine learning,molecular dynamic simulation and physiologically based absorption modeling(PBAM),to enhance andrographolide(AG)/cyclodextrins(CDs)formulation design.The light GBM prediction model we built before was utilized to predict AG/CDs inclusion's binding free energy.AG/γ-CD inclusion complexes showed the strongest binding affinity,which was experimentally validated by the phase solubility study.The molecular dynamic simulation was used to investigate the inclusion mechanism between AG andγ-CD,which was experimentally characterized by DSC,FTIR and NMR techniques.PBAM was applied to simulate the in vivo behavior of the formulations,which were validated by cell and animal experiments.Cell experiments revealed that the presence of D-α-Tocopherol polyethylene glycol succinate(TPGS)significantly increased the intracellular uptake of AG in MDCKMDR1 cells and the absorptive transport of AG in MDCK-MDR1 monolayers.The relative bioavailability of the AG-CD-TPGS ternary system in rats was increased to 2.6-fold and 1.59-fold compared with crude AG and commercial dropping pills,respectively.In conclusion,this is the first time to integrate various computational tools to develop a new AG-CD-TPGS ternary formulation with significant improvement of aqueous solubility,dissolution rate and bioavailability.The integrated computational tool is a novel and robust methodology to facilitate pharmaceutical formulation design.
基金This study was supported by National Natural Science Foundation of China(82173762)111 Project(B18035,China)the Key Research and Development Program of Science and Technology Department of Sichuan Province(2022JDJQ0050,2022YFS0334).
文摘Cancer immunotherapy has significantly flourished and revolutionized the limited conventional tumor therapies,on account of its good safety and long-term memory ability.Discouragingly,low patient response rates and potential immune-related side effects make it rather challenging to literally bring immunotherapy from bench to bedside.However,it has become evident that,although the immunosuppressive tumor microenvironment(TME)plays a pivotal role in facilitating tumor progression and metastasis,it also provides various potential targets for remodeling the immunosuppressive TME,which can consequently bolster the effectiveness of antitumor response and tumor suppression.Additionally,the particular characteristics of TME,in turn,can be exploited as avenues for designing diverse precise targeting nanomedicines.In general,it is of urgent necessity to deliver nanomedicines for remodeling the immunosuppressive TME,thus improving the therapeutic outcomes and clinical translation prospects of immunotherapy.Herein,we will illustrate several formation mechanisms of immunosuppressive TME.More importantly,a variety of strategies concerning remodeling immunosuppressive TME and strengthening patients'immune systems,will be reviewed.Ultimately,we will discuss the existing obstacles and future perspectives in the development of antitumor immunotherapy.Hopefully,the thriving bloom of immunotherapy will bring vibrancy to further exploration of comprehensive cancer treatment.
基金This study was supported by China Postdoctoral Science Foundation(Nos.2017M620159 and 2019T120345)National Natural Science Foundation of China(Nos.81772098 and 81801917),Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(No.20152227)+3 种基金Cross Research Project of Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine(No.JYJC202009)Shanghai Health Industry Clinical Research Special Project(No.20204Y0443)Shanghai Municipal Key Clinical Specialty(shslczdzk00901)Scientific Research Foundation of Shanghai Municipal Commission of Health and Family Planning(No.20154Y002).
文摘Photodynamic therapy(PDT)is an emerging therapeutic strategy for hypertrophic scars(HS),which is heavily dependent on reactive oxygen species(ROS)generation.However,the unsatisfactory delivery and excitation of 5-aminolevulinic acid(ALA,a commercial photosensitizer in dermatology)result in an insufficient ROS generation,and thus limit the clinical application of PDT treating HS(HS-PDT).Consequently,sophisticated transdermal co-delivery nanoethosomes(named A/A-ES)with ALA and Au nanotriangles(AuNTs)in cores are prepared via an in-situ seed-mediated growth method,and then applied to improve HS-PDT through localized surface plasmon resonance(LSPR)-enhanced ROS generation.A/A-ES display a satisfactory performance in co-delivery in HS tissue with sufficient protoporphyrin IX production and LSPR effect in cytoplasm,which is beneficial for ALA excitation as well as ROS generation.In vitrolvivo studies reveal that A/A-ES significantly improve HS-PDT in promoting to fibroblast apoptosis and collagen remodeling through LSPR-enhanced ROS generation.Therefore,this study provides a feasible strategy that integrates transdermal delivery and LSPR to enable the beneficial effects of HS-PDT through boosting the delivery and excitation of ALA.