Large-scale integration of wind power into a power system introduces uncertainties to its operation and planning,making the power system operation scenario highly diversified and variable.In conventional power system ...Large-scale integration of wind power into a power system introduces uncertainties to its operation and planning,making the power system operation scenario highly diversified and variable.In conventional power system planning,some key operation modes and most critical scenarios are typically analyzed to identify the weak and high-risk points in grid operation.While these scenarios may not follow traditional empirical patterns due to the introduction of large-scale wind power.In this paper,we propose a weighted clustering method to quickly identify a system’s extreme operation scenarios by considering the temporal variations and correlations between wind power and load to evaluate the stability and security for system planning.Specifically,based on an annual time-series data of wind power and load,a combined weighted clustering method is used to pick the typical scenarios of power grid operation,and the edge operation points far from the clustering center are extracted as the extreme scenarios.The contribution of fluctuations and capacities of different wind farms and loads to extreme scenarios are considered in the clustering process,to further improve the efficiency and rationality of the extreme-scenario extraction.A set of case studies was used to verify the performance of the method,providing an intuitive understanding of the extreme scenario variety under wind power integration.展开更多
Nanoprobes that offer both fluorescence imaging(FI)and magnetic resonance imaging(MRI)can provide supplementary information and hold synergistic advantages.However,synthesis of such dual-modality imaging probes that s...Nanoprobes that offer both fluorescence imaging(FI)and magnetic resonance imaging(MRI)can provide supplementary information and hold synergistic advantages.However,synthesis of such dual-modality imaging probes that simultaneously exhibit tunability of functional groups,high stability,great biocompatibility and desired dual-modality imaging results remains challenging.In this study,we used an amphiphilic block polymer from(ethylene glycol)methyl ether methacrylate(OEGMA)and N-(2-hydroxypropyl)methacrylamide(HPMA)derivatives as a carrier to conjugate a MR contrast agent,Gd-DOTA,and a two-photon fluorophore with an aggregation-induced emission(AIE)effect,TPBP,to construct a MR/two-photon fluorescence dual-modality contrast agent,Gd-DOTA-TPBP.Incorporation of gadolinium in the hydrophilic chain segment of the OEGMA-based carrier resulted in a high r_(1)value for Gd-DOTA-TPBP,revealing a great MR imaging resolution.The contrast agent specifically accumulated in the tumor region,allowing a long enhancement duration for vascular and tumor contrast-enhanced MR imaging.Meanwhile,coupling TPBP with AIE properties to the hydrophobic chain segment of the carrier not only improved its water solubility and reduced its cytotoxicity,but also significantly enhanced its imaging performance in an aqueous phase.Gd-DOTA-TPBP was also demonstrated to act as an excellent fluorescence probe for two-photon-excited bioimaging with higher resolution and greater sensitivity than MRI.Since high-resolution,complementary MRI/FI dual-modal images were acquired at both cellular and tissue levels in tumor-bearing mice after application of Gd-DOTA-TPBP,it has great potential in the early phase of disease diagnosis.展开更多
Despite the great potential of anti-PD-L1 antibodies for immunotherapy,their low response rate due to an immunosuppressive tumor microenvironment has hampered their application.To address this issue,we constructed a c...Despite the great potential of anti-PD-L1 antibodies for immunotherapy,their low response rate due to an immunosuppressive tumor microenvironment has hampered their application.To address this issue,we constructed a cell membrane-coated nanosystem(mB4S)to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor effect.In this system,Epirubicin(EPI)as an immunogenic cell death(ICD)inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes(STING)agonist was encapsulated into mB4S.After internalization of mB4S,EPI was acidic-responsively released to induce ICD,which was characterized by an increased level of calreticulin(CRT)exposure and enhanced ATP secretion.Meanwhile,diABZI effectively activated the STING pathway.Treatment with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells(DCs)and CD8+T cells,promoting cytokines secretion,up-regulating M1-like tumor-associated macrophages(TAMs)and down-regulating immunosuppressive myeloid-derived suppressor cells(MDSCs).Therefore,this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+T cells infiltration,creating an immuno-supportive microenvironment,thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.展开更多
Cancer cells could be eradicated by promoting generation of excessive intracellular reactive oxygen species(ROS)via emerging nanomedicines.However,tumor heterogeneity and poor penetration of nanomedicines often lead t...Cancer cells could be eradicated by promoting generation of excessive intracellular reactive oxygen species(ROS)via emerging nanomedicines.However,tumor heterogeneity and poor penetration of nanomedicines often lead to diverse levels of ROS production in the tumor site,and ROS at a low level promote tumor cell growth,thus diminishing the therapeutic effect of these nanomedicines.Herein,we construct an amphiphilic and block polymer-dendron conjugate-derived nanomedicine(Lap@pOEGMA-b-p(GFLG-Dendron-Ppa),GFLG-DP/Lap NPs)that incorporates a photosensitizer,Pyropheophorbide a(Ppa),for ROS therapy and Lapatinib(Lap)for molecular targeted therapy.Lap,an epidermal growth factor receptor(EGFR)inhibitor that plays a role in inhibiting cell growth and proliferation,is hypothesized to synergize with ROS therapy for effectively killing cancer cells.Our results suggest that the enzyme-sensitive polymeric conjugate,pOEGMA-b-p(GFLG-Dendron-Ppa)(GFLG-DP),releases in response to cathepsin B(CTSB)after entering the tumor tissue.Dendritic-Ppa has a strong adsorption capacity to tumor cell membranes,which promotes efficient penetration and long-term retention.Lap can also be efficiently delivered to internal tumor cells to play its role due to the increased vesicle activity.Laser irradiation of Ppa-containing tumor cells results in production of intracellular ROS that is sufficient for inducing cell apoptosis.Meanwhile,Lap efficiently inhibits proliferation of remaining viable cells even in deep tumor regions,thus generating a significant synergistic anti-tumor therapeutic effect.This novel strategy can be extended to the development of efficient membrane lipid-based therapies to effectively combat tumors.展开更多
To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosup-pressive cancers like triple-negative breast cancer(TNBC),induction of immunogenic cell death(ICD)at tumor sites ca...To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosup-pressive cancers like triple-negative breast cancer(TNBC),induction of immunogenic cell death(ICD)at tumor sites can increase the antigenicity and adjuvanticity to activate the immune microenvironment so that tumors become sensitive to the intervention of immune checkpoint inhibitors.Herein,a self-amplified biomimetic nanosystem,mEHGZ,was constructed by encapsulation of epirubicin(EPI),glucose oxidase(Gox)and hemin in ZIF-8 nanoparticles and coating of the nanoparticles with calreticulin(CRT)over-expressed tumor cell mem-brane.EPI acts as an ICD inducer,Gox and hemin medicate the cascade generation of reactive oxygen species(ROS)to strengthen the ICD effect,and CRT-rich membrane as“eat me”signal promote presentation of the released antigens by dendritic cells(DCs)to invoke the tumor-immunity cycle.The biomimetic delivery system displays an amplified ICD effect via Gox oxidation,hydroxyl radical generation and glutathione(GSH)depletion.The induced potent ICD effect promotes DCs maturation and cytotoxic T lymphocytes(CTLs)infiltration,reversing an immunosuppressive tumor microenvironment to an immunoresponsive one.Treatment with the nanosystem in combination with anti-PD-L1 antibody results in distinctive inhibition of tumor growth and lung metastasis,supporting that a potent ICD effect can significantly boost the therapeutic efficacy of the anti-PD-L1 antibody.This self-amplified biomimetic nanoplatform offers a promising means of raising the response rate of immune checkpoint inhibitors.展开更多
The authors regret the incorrect publication of corresponding authors for the article.The corresponding authors have been updated as Hongyan Zhu(hyzhu_hmrrc@126.com)and Kui Luo(luokui@scu.edu.cn),and the same should b...The authors regret the incorrect publication of corresponding authors for the article.The corresponding authors have been updated as Hongyan Zhu(hyzhu_hmrrc@126.com)and Kui Luo(luokui@scu.edu.cn),and the same should be updated in the supplementary file as well.展开更多
Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug(molecular weight,MW: 93.5 k Da) was produced by ...Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug(molecular weight,MW: 93.5 k Da) was produced by reversible addition-fragmentation chain transfer(RAFT) polymerization. The amphiphilic block polymer-doxorubicin(DOX) prodrug was employed to deliver a hydrophobic photosensitizer(PS), chlorin e6(Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione(GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 k Da in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4 T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition(TGI,58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.展开更多
Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer.Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs ...Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer.Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment.A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate,conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a(Ppa)with a branched glycopolymer.The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B,and PTX was simultaneously released to exert its therapeutic effect.The theranostic nanomedicine,branched glycopolymer-PTX-DOTA-Gd,had an extended circulation time,enhanced accumulation in tumors,and excellent biocompatibility with significantly reduced gadolinium ion(Gd3+)retention after 96 h post-injection.Enhanced imaging contrast up to 24 h post-injection and excellent antitumor efficacy with a tumor inhibition rate more than 90%were achieved from glycopolymer-PTX-DOTA-Gd without obvious systematic toxicity.This branched polymeric prodrug-based nanomedicine is very promising for safe and effective diagnosis and treatment of cancer.展开更多
Cancer immunotherapy is an effective antitumor approach through activating immune systems to eradicate tumors by immunotherapeutics.However,direct administration of“naked”immunotherapeutic agents(such as nucleic aci...Cancer immunotherapy is an effective antitumor approach through activating immune systems to eradicate tumors by immunotherapeutics.However,direct administration of“naked”immunotherapeutic agents(such as nucleic acids,cytokines,adjuvants or antigens without delivery vehicles)often results in:(1)an unsatisfactory efficacy due to suboptimal pharmacokinetics;(2)strong toxic and side effects due to low targeting(or off-target)efficiency.To overcome these shortcomings,a series of polysaccharide-based nanoparticles have been developed to carry immunotherapeutics to enhance antitumor immune responses with reduced toxicity and side effects.Polysaccharides are a family of natural polymers that hold unique physicochemical and biological properties,as they could interact with immune system to stimulate an enhanced immune response.Their structures offer versatility in synthesizing multifunctional nanocomposites,which could be chemically modified to achieve high stability and bioavailability for delivering therapeutics into tumor tissues.This review aims to highlight recent advances in polysaccharide-based nanomedicines for cancer immunotherapy and propose new perspectives on the use of polysaccharide-based immunotherapeutics.展开更多
Dendron-polymer-based nanoscale and stimuli-responsive drug delivery systems have shown great promise in tumor-targeting accumulation without significant toxicity.Here we report a dendronized polymer-doxorubicin(DOX)h...Dendron-polymer-based nanoscale and stimuli-responsive drug delivery systems have shown great promise in tumor-targeting accumulation without significant toxicity.Here we report a dendronized polymer-doxorubicin(DOX)hybrid(DPDH)with an improved in vivo drug delivery efficiency for cancer therapy compared with a linear polymer-DOX conjugate(LPDC).The in vitro drug release profile of DOX indicates that DPDH displays pH-responsive drug release due to cleavage of hydrazone bonds since a greater amount of DOX is released at pH 5.2 at a faster rate than at pH 7.4.DPDH efficiently enters 4 T1 cells and releases DOX to induce cytotoxicity and apoptosis.Owing to the dendronzied structure,DPDH has a significantly longer blood circulation time than LPDC.DPDH substantially enhances the therapeutic efficacy to suppress tumor growth in a 4 T1 mammary cancer model than LPDC as well as free drug,evidenced from tumor growth inhibition,TUNEL assessment and histological analysis.Biosafety of DPDH is also confirmed from hemolysis,body weight shifts during treatment and pathological analysis.This study demonstrates the use of dendronized polymer-DOX hybrids for specific drug molecules is a promising approach for drug delivery.展开更多
There is increasing interest in the evaluation of wind turbine control capabilities for providing grid support.Power hardware in the loop(PHIL)simulation is an advanced method that can be used for studying the interac...There is increasing interest in the evaluation of wind turbine control capabilities for providing grid support.Power hardware in the loop(PHIL)simulation is an advanced method that can be used for studying the interaction of hardware with the power network,as the scaled-down actual wind turbine is connected with a simulated system through an amplifier.Special consideration must be made in the design of the PHIL platform to ensure that the system is stable and yields accurate results.This paper presents a method for stabilizing the PHIL interface and improving the accuracy of PHIL simulation in a real-time application.The method factors in both the power and voltage scaling level,and a phase compensation scheme.It uses the reactive power control capability of the wind turbine inverter to eliminate the phase shift imposed by the feedback current filter.This is accomplished with no negative impact on the dynamic behavior of the wind turbine.The PHIL simulation results demonstrate the effectiveness of the proposed stability analysis method and phase compensation scheme.The strength of the platform is demonstrated by extending the simulation method to wind turbine control validation.展开更多
Liver transplantation(LTx)is an established option for the treatment of end-stage liver disease,acute liver failure,and hepatic malignancies(1-3).Despite significant advances in clinical practice and scientific resear...Liver transplantation(LTx)is an established option for the treatment of end-stage liver disease,acute liver failure,and hepatic malignancies(1-3).Despite significant advances in clinical practice and scientific research on LTx,liver allograft dysfunction remains a significant clinical problem.Early allograft dysfunction(EAD)is a milder form of primary graft dysfunction that correlates with postoperative complications,higher mortality rates,and decreased graft survival(4).The frequency of EAD ranges from 15%to 30%after LTx from donors after brain death(DBD),reaching 68.4%after LTx from donors after cardiac death(DCD)(5).For living donor liver transplantation(LDLT),the prevalence of EAD is comparatively low,accounting for 18.1%of the recipients in our transplant center(4).展开更多
Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells.Herein,we constructed a PEGylated dendritic ep...Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells.Herein,we constructed a PEGylated dendritic epirubicin(Epi)prodrug(Epi-P4D)to regulate the metabolism of cancer-associated fibroblasts(CAFs),thus enhancing Epi penetration into both multicellular tumor spheroids(MTSs)and tumor tissues in mouse colon cancer(CT26),mouse breast cancer(4T1)and human breast cancer(MDA-MB-231)models.Enhanced cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin,α-SMA,and collagen secretion.Besides,thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell(DC)maturation and subsequent immune activation,including elevating the CD4^(+)T cell population,reducing CD4^(+)and CD8^(+)T cell hyperactivation and exhaustion,and amplifying the natural killer(NK)cell proportion and effectively activating them.As a result,this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.展开更多
基金supported by Innovation Fund Program of China Electric Power Research Institute(NY83-19-003)
文摘Large-scale integration of wind power into a power system introduces uncertainties to its operation and planning,making the power system operation scenario highly diversified and variable.In conventional power system planning,some key operation modes and most critical scenarios are typically analyzed to identify the weak and high-risk points in grid operation.While these scenarios may not follow traditional empirical patterns due to the introduction of large-scale wind power.In this paper,we propose a weighted clustering method to quickly identify a system’s extreme operation scenarios by considering the temporal variations and correlations between wind power and load to evaluate the stability and security for system planning.Specifically,based on an annual time-series data of wind power and load,a combined weighted clustering method is used to pick the typical scenarios of power grid operation,and the edge operation points far from the clustering center are extracted as the extreme scenarios.The contribution of fluctuations and capacities of different wind farms and loads to extreme scenarios are considered in the clustering process,to further improve the efficiency and rationality of the extreme-scenario extraction.A set of case studies was used to verify the performance of the method,providing an intuitive understanding of the extreme scenario variety under wind power integration.
基金supported by National Natural Science Foundation of China(52073193,51873120,81621003,51903173)1⋅3⋅5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21013)+1 种基金Science and Technology Program of Sichuan province(2020YJ0231)China Postdoctoral Science Foundation(2021M692255).
文摘Nanoprobes that offer both fluorescence imaging(FI)and magnetic resonance imaging(MRI)can provide supplementary information and hold synergistic advantages.However,synthesis of such dual-modality imaging probes that simultaneously exhibit tunability of functional groups,high stability,great biocompatibility and desired dual-modality imaging results remains challenging.In this study,we used an amphiphilic block polymer from(ethylene glycol)methyl ether methacrylate(OEGMA)and N-(2-hydroxypropyl)methacrylamide(HPMA)derivatives as a carrier to conjugate a MR contrast agent,Gd-DOTA,and a two-photon fluorophore with an aggregation-induced emission(AIE)effect,TPBP,to construct a MR/two-photon fluorescence dual-modality contrast agent,Gd-DOTA-TPBP.Incorporation of gadolinium in the hydrophilic chain segment of the OEGMA-based carrier resulted in a high r_(1)value for Gd-DOTA-TPBP,revealing a great MR imaging resolution.The contrast agent specifically accumulated in the tumor region,allowing a long enhancement duration for vascular and tumor contrast-enhanced MR imaging.Meanwhile,coupling TPBP with AIE properties to the hydrophobic chain segment of the carrier not only improved its water solubility and reduced its cytotoxicity,but also significantly enhanced its imaging performance in an aqueous phase.Gd-DOTA-TPBP was also demonstrated to act as an excellent fluorescence probe for two-photon-excited bioimaging with higher resolution and greater sensitivity than MRI.Since high-resolution,complementary MRI/FI dual-modal images were acquired at both cellular and tissue levels in tumor-bearing mice after application of Gd-DOTA-TPBP,it has great potential in the early phase of disease diagnosis.
基金This work was supported by National Natural Science Foundation of China(32271445,52073193,and 82202322)National Science and Technology Major Project of China(2023YFB3810004)+2 种基金1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21013,China)the Sichuan Science and Technology Program(2023NSFSC1592,China),the China Postdoctoral Science Foundation(2021M692255,China)the Post-Doctor Research Project,West China Hospital,Sichuan University(2020HXBH094,China).
文摘Despite the great potential of anti-PD-L1 antibodies for immunotherapy,their low response rate due to an immunosuppressive tumor microenvironment has hampered their application.To address this issue,we constructed a cell membrane-coated nanosystem(mB4S)to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor effect.In this system,Epirubicin(EPI)as an immunogenic cell death(ICD)inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes(STING)agonist was encapsulated into mB4S.After internalization of mB4S,EPI was acidic-responsively released to induce ICD,which was characterized by an increased level of calreticulin(CRT)exposure and enhanced ATP secretion.Meanwhile,diABZI effectively activated the STING pathway.Treatment with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells(DCs)and CD8+T cells,promoting cytokines secretion,up-regulating M1-like tumor-associated macrophages(TAMs)and down-regulating immunosuppressive myeloid-derived suppressor cells(MDSCs).Therefore,this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+T cells infiltration,creating an immuno-supportive microenvironment,thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.
基金supported by National Natural Science Foundation of China(52073193,51873120,81621003,52203182,32071284)National Key Research and Development Program of China(2022YFC2009900)+2 种基金1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21013)Research Funds in West China Hospital of Sichuan University(2020HXBH072)China Postdoctoral Science Foundation(2019TQ0220,2022M712225,2022T150446).
文摘Cancer cells could be eradicated by promoting generation of excessive intracellular reactive oxygen species(ROS)via emerging nanomedicines.However,tumor heterogeneity and poor penetration of nanomedicines often lead to diverse levels of ROS production in the tumor site,and ROS at a low level promote tumor cell growth,thus diminishing the therapeutic effect of these nanomedicines.Herein,we construct an amphiphilic and block polymer-dendron conjugate-derived nanomedicine(Lap@pOEGMA-b-p(GFLG-Dendron-Ppa),GFLG-DP/Lap NPs)that incorporates a photosensitizer,Pyropheophorbide a(Ppa),for ROS therapy and Lapatinib(Lap)for molecular targeted therapy.Lap,an epidermal growth factor receptor(EGFR)inhibitor that plays a role in inhibiting cell growth and proliferation,is hypothesized to synergize with ROS therapy for effectively killing cancer cells.Our results suggest that the enzyme-sensitive polymeric conjugate,pOEGMA-b-p(GFLG-Dendron-Ppa)(GFLG-DP),releases in response to cathepsin B(CTSB)after entering the tumor tissue.Dendritic-Ppa has a strong adsorption capacity to tumor cell membranes,which promotes efficient penetration and long-term retention.Lap can also be efficiently delivered to internal tumor cells to play its role due to the increased vesicle activity.Laser irradiation of Ppa-containing tumor cells results in production of intracellular ROS that is sufficient for inducing cell apoptosis.Meanwhile,Lap efficiently inhibits proliferation of remaining viable cells even in deep tumor regions,thus generating a significant synergistic anti-tumor therapeutic effect.This novel strategy can be extended to the development of efficient membrane lipid-based therapies to effectively combat tumors.
基金National Natural Science Foundation of China(52073193,51873120 and 81621003)1‧3‧5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21013)。
文摘To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosup-pressive cancers like triple-negative breast cancer(TNBC),induction of immunogenic cell death(ICD)at tumor sites can increase the antigenicity and adjuvanticity to activate the immune microenvironment so that tumors become sensitive to the intervention of immune checkpoint inhibitors.Herein,a self-amplified biomimetic nanosystem,mEHGZ,was constructed by encapsulation of epirubicin(EPI),glucose oxidase(Gox)and hemin in ZIF-8 nanoparticles and coating of the nanoparticles with calreticulin(CRT)over-expressed tumor cell mem-brane.EPI acts as an ICD inducer,Gox and hemin medicate the cascade generation of reactive oxygen species(ROS)to strengthen the ICD effect,and CRT-rich membrane as“eat me”signal promote presentation of the released antigens by dendritic cells(DCs)to invoke the tumor-immunity cycle.The biomimetic delivery system displays an amplified ICD effect via Gox oxidation,hydroxyl radical generation and glutathione(GSH)depletion.The induced potent ICD effect promotes DCs maturation and cytotoxic T lymphocytes(CTLs)infiltration,reversing an immunosuppressive tumor microenvironment to an immunoresponsive one.Treatment with the nanosystem in combination with anti-PD-L1 antibody results in distinctive inhibition of tumor growth and lung metastasis,supporting that a potent ICD effect can significantly boost the therapeutic efficacy of the anti-PD-L1 antibody.This self-amplified biomimetic nanoplatform offers a promising means of raising the response rate of immune checkpoint inhibitors.
文摘The authors regret the incorrect publication of corresponding authors for the article.The corresponding authors have been updated as Hongyan Zhu(hyzhu_hmrrc@126.com)and Kui Luo(luokui@scu.edu.cn),and the same should be updated in the supplementary file as well.
基金financially supported by the National Natural Science Foundation of China(82073790,51873120,51673127,and 81621003)1·3·5 project for disciplines of excellence,West China Hospital,Sichuan University,China(ZYJC21013,ZYGD18028)。
文摘Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug(molecular weight,MW: 93.5 k Da) was produced by reversible addition-fragmentation chain transfer(RAFT) polymerization. The amphiphilic block polymer-doxorubicin(DOX) prodrug was employed to deliver a hydrophobic photosensitizer(PS), chlorin e6(Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione(GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 k Da in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4 T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition(TGI,58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.
基金financially supported by the National Natural Science Foundation of China(Nos.51873120,51673127,and 81621003)Department of Science and Technology of Sichuan Province(Nos.2018JY0574,2017SZ0006,18GJHZ0139,and 2018HH0006,China)1·3·5 Research Funds in West China Hospital of Sichuan University(ZYGD18028,China)
文摘Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer.Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment.A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate,conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a(Ppa)with a branched glycopolymer.The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B,and PTX was simultaneously released to exert its therapeutic effect.The theranostic nanomedicine,branched glycopolymer-PTX-DOTA-Gd,had an extended circulation time,enhanced accumulation in tumors,and excellent biocompatibility with significantly reduced gadolinium ion(Gd3+)retention after 96 h post-injection.Enhanced imaging contrast up to 24 h post-injection and excellent antitumor efficacy with a tumor inhibition rate more than 90%were achieved from glycopolymer-PTX-DOTA-Gd without obvious systematic toxicity.This branched polymeric prodrug-based nanomedicine is very promising for safe and effective diagnosis and treatment of cancer.
基金This work was supported by the National Natural Science Foundation of China(51873120,51673127,81621003)National Science and Technology Major Project of China(2017ZX09304023)+1 种基金Ruilong Sheng,Helena Tomas and Joao Rodrigues appreciate the support from Fundaçao para a Ciencia e a Tecnologia(Base Fund UIDB/00674/2020,CQM,Portuguese Government Funds)ARDITI-Agencia Regional para o Desenvolvimento da Investigaçao Tecnologia e Inovaçao through the project M1420-01-0145-FEDER-000005-Centro de Química da Madeira-CQM+(Madeira 14-20 Program)and ARDITI-2017-ISG-003.
文摘Cancer immunotherapy is an effective antitumor approach through activating immune systems to eradicate tumors by immunotherapeutics.However,direct administration of“naked”immunotherapeutic agents(such as nucleic acids,cytokines,adjuvants or antigens without delivery vehicles)often results in:(1)an unsatisfactory efficacy due to suboptimal pharmacokinetics;(2)strong toxic and side effects due to low targeting(or off-target)efficiency.To overcome these shortcomings,a series of polysaccharide-based nanoparticles have been developed to carry immunotherapeutics to enhance antitumor immune responses with reduced toxicity and side effects.Polysaccharides are a family of natural polymers that hold unique physicochemical and biological properties,as they could interact with immune system to stimulate an enhanced immune response.Their structures offer versatility in synthesizing multifunctional nanocomposites,which could be chemically modified to achieve high stability and bioavailability for delivering therapeutics into tumor tissues.This review aims to highlight recent advances in polysaccharide-based nanomedicines for cancer immunotherapy and propose new perspectives on the use of polysaccharide-based immunotherapeutics.
基金supported financially by National Natural Science Foundation of China(51673127,51873120,81621003,81801820)Department of Science and Technology of Sichuan Province(2018HH0006)+3 种基金Ministry of Science and Technology of the People’s Republic of China(2015DFE52780)China Postdoctoral Science Foundation(2018M643493)1·3·5 Research Funds in West China Hospital of Sichuan University(ZYGD18028)the Fundamental Research Funds for the Central Universities(2018SCU12032)。
文摘Dendron-polymer-based nanoscale and stimuli-responsive drug delivery systems have shown great promise in tumor-targeting accumulation without significant toxicity.Here we report a dendronized polymer-doxorubicin(DOX)hybrid(DPDH)with an improved in vivo drug delivery efficiency for cancer therapy compared with a linear polymer-DOX conjugate(LPDC).The in vitro drug release profile of DOX indicates that DPDH displays pH-responsive drug release due to cleavage of hydrazone bonds since a greater amount of DOX is released at pH 5.2 at a faster rate than at pH 7.4.DPDH efficiently enters 4 T1 cells and releases DOX to induce cytotoxicity and apoptosis.Owing to the dendronzied structure,DPDH has a significantly longer blood circulation time than LPDC.DPDH substantially enhances the therapeutic efficacy to suppress tumor growth in a 4 T1 mammary cancer model than LPDC as well as free drug,evidenced from tumor growth inhibition,TUNEL assessment and histological analysis.Biosafety of DPDH is also confirmed from hemolysis,body weight shifts during treatment and pathological analysis.This study demonstrates the use of dendronized polymer-DOX hybrids for specific drug molecules is a promising approach for drug delivery.
基金supported in part by the National Basic Research Program of China(973 Program)under Grant 2012CB215105.
文摘There is increasing interest in the evaluation of wind turbine control capabilities for providing grid support.Power hardware in the loop(PHIL)simulation is an advanced method that can be used for studying the interaction of hardware with the power network,as the scaled-down actual wind turbine is connected with a simulated system through an amplifier.Special consideration must be made in the design of the PHIL platform to ensure that the system is stable and yields accurate results.This paper presents a method for stabilizing the PHIL interface and improving the accuracy of PHIL simulation in a real-time application.The method factors in both the power and voltage scaling level,and a phase compensation scheme.It uses the reactive power control capability of the wind turbine inverter to eliminate the phase shift imposed by the feedback current filter.This is accomplished with no negative impact on the dynamic behavior of the wind turbine.The PHIL simulation results demonstrate the effectiveness of the proposed stability analysis method and phase compensation scheme.The strength of the platform is demonstrated by extending the simulation method to wind turbine control validation.
基金the Sichuan Science and Technology Program(No.2019YFG0036)the Sichuan Province Key Research and Development Project(No.2020YFS0134)+1 种基金the Major National Science and Technology Special Projects(No.2017ZX10203205-005-002 and No.2017ZX10203205-001-004)the National Natural Science Foundation of China(No.81470037 and No.81770653).
文摘Liver transplantation(LTx)is an established option for the treatment of end-stage liver disease,acute liver failure,and hepatic malignancies(1-3).Despite significant advances in clinical practice and scientific research on LTx,liver allograft dysfunction remains a significant clinical problem.Early allograft dysfunction(EAD)is a milder form of primary graft dysfunction that correlates with postoperative complications,higher mortality rates,and decreased graft survival(4).The frequency of EAD ranges from 15%to 30%after LTx from donors after brain death(DBD),reaching 68.4%after LTx from donors after cardiac death(DCD)(5).For living donor liver transplantation(LDLT),the prevalence of EAD is comparatively low,accounting for 18.1%of the recipients in our transplant center(4).
基金supported by the National Science and Technology Major Project of China(2023YFB3810004)the National Natural Science Foundation of China(32271445,52103175,32271382,32101145)+4 种基金the National Key Research and Development Program of China(2022YFC2009900)Department of Science and Technology of Sichuan Province(24NSFJQ0167,China)1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21013,China)Post-Doctor Research Project,West China Hospital,Sichuan University(2021HXBH055,2021HXBH057,China)China Postdoctoral Science Foundation(2021M692314).
文摘Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells.Herein,we constructed a PEGylated dendritic epirubicin(Epi)prodrug(Epi-P4D)to regulate the metabolism of cancer-associated fibroblasts(CAFs),thus enhancing Epi penetration into both multicellular tumor spheroids(MTSs)and tumor tissues in mouse colon cancer(CT26),mouse breast cancer(4T1)and human breast cancer(MDA-MB-231)models.Enhanced cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin,α-SMA,and collagen secretion.Besides,thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell(DC)maturation and subsequent immune activation,including elevating the CD4^(+)T cell population,reducing CD4^(+)and CD8^(+)T cell hyperactivation and exhaustion,and amplifying the natural killer(NK)cell proportion and effectively activating them.As a result,this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.