Polymyxin B,which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections,became available in China in Dec.2017.As dose adjustments are based solely on clinical experience of risk t...Polymyxin B,which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections,became available in China in Dec.2017.As dose adjustments are based solely on clinical experience of risk toxicity,treatment failure,and emergence of resistance,there is an urgent clinical need to perform therapeutic drug monitoring(TDM)to optimize the use of polymyxin B.It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use.We report a consensus on TDM guidelines for polymyxin B,as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society.The consensus panel was composed of clinicians,pharmacists,and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations,sample collection,reporting,and explanation of TDM results.The guidelines provide the first-ever consensus on conducting TDM of polymyxin B,and are intended to guide optimal clinical use.展开更多
BACKGROUND Chemotherapy is an essential treatment for colorectal cancer(CRC)patients after surgery,but many patients do not benefit from chemotherapy because tumour heterogeneity results in varied responses.AIM To stu...BACKGROUND Chemotherapy is an essential treatment for colorectal cancer(CRC)patients after surgery,but many patients do not benefit from chemotherapy because tumour heterogeneity results in varied responses.AIM To study the effectiveness of in vitro chemosensitivity tests adenosine tripho-sphate-based tumour chemotherapy sensitivity test(ATP-TCA)for tailoring po-stoperative chemotherapy regimens for patients with CRC.METHODS Between January 2015 to December 2021,a total of 1549 CRC patients underwent surgery and in vitro chemosensitivity testing using ATP-TCA.A subset of 405 patients who met the survival assessment criteria were followed to collect data on overall survival(OS)and disease-free survival(DFS).Cox regression analysis revealed independent prognostic factors that affect OS and DFS for those re-ceiving oxaliplatin(L-OPH)and fluoropyrimidine-based regimens,aiding in the development of clinical predictive models.The relationships between the ATP-TCA results and clinical outcomes were analysed using the Kaplan-Meier method.RESULTS Tumour heterogeneity and resistance to multiple drugs were observed in 1549 patients.The sensitivity to 5-fluorouracil(5-FU)combined with L-OPH was tested among 1474 of these patients,yielding a sensitivity rate of 11.9%.ATP-TCA results were identified as an independent prognostic factor for DFS[P=0.002,hazard ratio(95%confidence interval):4.98(1.81-13.72)]in patients with resectable CRC.Compared with drug-resistant patients,sensitive CRC patients treated with 5-FU and L-OPH had significantly prolonged DFS(P=0.027).Further Kaplan-Meier analysis indicated that ATP-TCA sensitivity was significantly associated with improved OS(P=0.048)and DFS(P=0.003)in patients with stage III CRC.CONCLUSION The response of CRC patients to the combination regimen of 5-FU and L-OPH is heterogeneous.This study confirmed that the ATP-TCA is a valuable tool for predicting clinical outcomes,such as DFS,in patients with resectable CRC receiving chemotherapy.Although further validation with multicentre data is still necessary,these findings support that the ATP-TCA may function as a guiding tool for personalized chemotherapy administration,thereby optimizing treatment opportunities for patients.展开更多
Targeted drug delivery with spatiotemporal control is critical for potent cancer therapy,yet inadequate subcellular delivery remains a major obstacle for DNA-targeted therapeutics due to multiple intracellular barrier...Targeted drug delivery with spatiotemporal control is critical for potent cancer therapy,yet inadequate subcellular delivery remains a major obstacle for DNA-targeted therapeutics due to multiple intracellular barriers.Herein,we report a photo-responsive polyprodrug supramolecular assembly to yield self-accelerated subcellular delivery of therapeutic cargoes for synergistic photochemotherapy against triple-negative breast cancer.The designed polyprodrug bears cleavable camptothecin pendants via thioketal-carbonate linkers and co-assembles with amphiphilic photosensitizers into ultrasmall supramolecular assembly,thereby affording sustained cargo release and enhanced singlet oxygen generation due to J-aggregate engineering of the photosensitizer within the assembly.Upon near-infrared light irradiation,the assembly elicits light-programmable drug release and lysosomal membrane disruption to facilitate rapid drug cytosolic translocation,followed by increased nuclear envelope permeability through lamin B1 downregulation and lipid peroxidation,thereby accelerating the permeation of cytosolic cargoes into the nucleus.Consequently,the self-accelerated intranuclear accumulation results in the eradication of intractable tumor through synergistic photochemotherapy.This study demonstrates a chemically programmed strategy for spatiotemporally-controlled subcellular delivery,providing a feasible avenue for highly effective cancer therapy.展开更多
B7 homolog 3(B7-H3)has attracted much attention in glioblastoma(GBM)radioimmunotherapy(RIT)due to its abnormally high expression on tumor cells.In this study,we report that two specific humanized anti-human B7-H3 anti...B7 homolog 3(B7-H3)has attracted much attention in glioblastoma(GBM)radioimmunotherapy(RIT)due to its abnormally high expression on tumor cells.In this study,we report that two specific humanized anti-human B7-H3 antibodies(hu4G4 and hu4H12)derived from mouse anti-human B7-H3 antibodies that were generated by computer-aided design and exclusively recognize membrane expression of B7-H3 by human glioma cells,Hu4G4 and hu4H12 were radiolabeled with^(89)Zr for RIT antibody screening.Micro-positron emission tomography(PET)imaging,biodistribution and pharmacokinetic(PK)analyses of^(89)Zr-labeled antibodies were performed in U87-xenografted models.^(125)I labelling of the antibodies for single-photon emission computed tomography(SPECT)imaging was also used to investigate the biological behavior of the antibodies in vivo.Fu rthermore,the pharmacodynamic(PD)of the^(131)Ilabeled antibodies were evaluated in U87-xenografted mice and GL261 Red-FLuc-B7-H3 in situ glioma tumor models.Micro-PET imaging and biodistribution analysis with a gamma counter showed that^(89)Zr-deferoxamine(DFO)-hu4G4 had higher tumor targeting performance with lower liver uptake than^(89)Zr-DFO-(hu4H12,immunoglobulin G(IgG)).The biodistribution results of^(125)I-SPECT imaging were similar to those of^(89)Zr-PET imaging,though the biodistribution in long bone joints and the thyroid varied.The PD analysis results indicated that^(131)I-hu4G4 had an excellent therapeutic effect and high safety with no apparent toxicity.Interestingly,^(131)I-hu4G4 improved the tumor vasculature in tissues with higher expression of collagen typeⅣand platelet-derived growth factor receptorβ(PDGFR-β)compared with control treatment,as determined by immunofluorescence(IF),which contributed to inhibiting tumor growth.Taken together,our data indicate that hu4G4 exhibits good tumor targeting and specificity,achieves low nonspecific concentrations in normal tissues,and has acceptable PK characteristics.^(131)I-hu4G4 also exerts effective antitumor effects with an ideal safety profile.Therefore,we expect hu4G4 to be an excellent antibody for the development of GBM RIT.展开更多
Cancer vaccine efficacy relies on T cells eliciting tumor-specific adaptive immunity,with antigen-presenting cells,particularly dendritic cells(DCs),playing a crucial role.After capturing antigens,DCs migrate to lymph...Cancer vaccine efficacy relies on T cells eliciting tumor-specific adaptive immunity,with antigen-presenting cells,particularly dendritic cells(DCs),playing a crucial role.After capturing antigens,DCs migrate to lymph nodes,where they present antigens to naïve T cells and activate B and natural killer(NK)cells,thereby strengthening anti-tumor immune responses.However,limitations in immune adjuvants and insufficient antigen presentation hinder DCs migration,reducing vaccine effectiveness.This study introduces an outer membrane vesicle(OMV)-based platform engineered to express Vibrio vulnificus flagellin B(FlaB),a Toll-like receptor 5(TLR5)agonist.FlaB effectively activates DCs,enhances interactions with T cells,provides robust costimulatory signals,and promotes cytotoxic CD8^(+)T cell differentiation.Compared to unmodified OMV-Ag,the antigen-loaded OMV-FlaB-Ag nanovaccine significantly enhances DC function,eliciting potent antitumor responses and delaying tumor progression across multiple models.When combined with immune checkpoint inhibitors,it further amplifies antitumor immunity,markedly suppressing tumor growth and improving therapeutic outcomes.展开更多
基金the Shanghai Leading Talents Award,Shanghai Municipal Health Commission(No.LJ2016-01)the Clinical Research Plan of Shanghai Hospital Development Center(No.SHDC2022CRW004)。
文摘Polymyxin B,which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections,became available in China in Dec.2017.As dose adjustments are based solely on clinical experience of risk toxicity,treatment failure,and emergence of resistance,there is an urgent clinical need to perform therapeutic drug monitoring(TDM)to optimize the use of polymyxin B.It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use.We report a consensus on TDM guidelines for polymyxin B,as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society.The consensus panel was composed of clinicians,pharmacists,and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations,sample collection,reporting,and explanation of TDM results.The guidelines provide the first-ever consensus on conducting TDM of polymyxin B,and are intended to guide optimal clinical use.
基金Supported by the National Natural Science Foundation of China,No.U24A20765 and No.T2321005Jiangsu Provincial Science and Technology Plan Special Fund,No.BM2023003+5 种基金Jiangsu Provincial Medical Key Discipline,No.ZDXK202247the Priority Academic Program Development of the Jiangsu Higher Education InstitutesJiangsu Engineering Research Center on Drug Evaluation and Translation of Organoids/Organ Chip(2024)the Science and Technology Plan of Suzhou,No.SKYD2023183the Research Project Established by Chinese Pharmaceutical Association Hospital Pharmacy Department,No.CPA-Z05-ZC-2023002Gusu Health Talent Research Project,No.GSWS2022015.
文摘BACKGROUND Chemotherapy is an essential treatment for colorectal cancer(CRC)patients after surgery,but many patients do not benefit from chemotherapy because tumour heterogeneity results in varied responses.AIM To study the effectiveness of in vitro chemosensitivity tests adenosine tripho-sphate-based tumour chemotherapy sensitivity test(ATP-TCA)for tailoring po-stoperative chemotherapy regimens for patients with CRC.METHODS Between January 2015 to December 2021,a total of 1549 CRC patients underwent surgery and in vitro chemosensitivity testing using ATP-TCA.A subset of 405 patients who met the survival assessment criteria were followed to collect data on overall survival(OS)and disease-free survival(DFS).Cox regression analysis revealed independent prognostic factors that affect OS and DFS for those re-ceiving oxaliplatin(L-OPH)and fluoropyrimidine-based regimens,aiding in the development of clinical predictive models.The relationships between the ATP-TCA results and clinical outcomes were analysed using the Kaplan-Meier method.RESULTS Tumour heterogeneity and resistance to multiple drugs were observed in 1549 patients.The sensitivity to 5-fluorouracil(5-FU)combined with L-OPH was tested among 1474 of these patients,yielding a sensitivity rate of 11.9%.ATP-TCA results were identified as an independent prognostic factor for DFS[P=0.002,hazard ratio(95%confidence interval):4.98(1.81-13.72)]in patients with resectable CRC.Compared with drug-resistant patients,sensitive CRC patients treated with 5-FU and L-OPH had significantly prolonged DFS(P=0.027).Further Kaplan-Meier analysis indicated that ATP-TCA sensitivity was significantly associated with improved OS(P=0.048)and DFS(P=0.003)in patients with stage III CRC.CONCLUSION The response of CRC patients to the combination regimen of 5-FU and L-OPH is heterogeneous.This study confirmed that the ATP-TCA is a valuable tool for predicting clinical outcomes,such as DFS,in patients with resectable CRC receiving chemotherapy.Although further validation with multicentre data is still necessary,these findings support that the ATP-TCA may function as a guiding tool for personalized chemotherapy administration,thereby optimizing treatment opportunities for patients.
基金supported by the National Natural Science Foundation of China(52125304,32330060,52473316,52573342,and 52503383)National Key R&D Program of China(2022YFA1206000)+7 种基金Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD),Key R&D Plan of Jiangsu Province(BE2022724)Gusu Innovation and Entrepreneurship Leading Talent Plan(ZXL2022508 and ZXL2023211)Project of State Key Laboratory of Radiation Medicine and Protection Soochow University(GZN1202301)Interdisciplinary Basic Frontier Innovation Program of Suzhou Medical College of Soochow University(YXY2303024 and YXY2304073)Natural Science Foundation of the Jiangsu Higher Education Institutions of China(23KJB350007)China Postdoctoral Science Foundation(2023TQ0234)Jiangsu Province Excellent Postdoctoral Program(2023ZB296)Postdoctoral Fellowship Program of CPSF(GZC20231897).
文摘Targeted drug delivery with spatiotemporal control is critical for potent cancer therapy,yet inadequate subcellular delivery remains a major obstacle for DNA-targeted therapeutics due to multiple intracellular barriers.Herein,we report a photo-responsive polyprodrug supramolecular assembly to yield self-accelerated subcellular delivery of therapeutic cargoes for synergistic photochemotherapy against triple-negative breast cancer.The designed polyprodrug bears cleavable camptothecin pendants via thioketal-carbonate linkers and co-assembles with amphiphilic photosensitizers into ultrasmall supramolecular assembly,thereby affording sustained cargo release and enhanced singlet oxygen generation due to J-aggregate engineering of the photosensitizer within the assembly.Upon near-infrared light irradiation,the assembly elicits light-programmable drug release and lysosomal membrane disruption to facilitate rapid drug cytosolic translocation,followed by increased nuclear envelope permeability through lamin B1 downregulation and lipid peroxidation,thereby accelerating the permeation of cytosolic cargoes into the nucleus.Consequently,the self-accelerated intranuclear accumulation results in the eradication of intractable tumor through synergistic photochemotherapy.This study demonstrates a chemically programmed strategy for spatiotemporally-controlled subcellular delivery,providing a feasible avenue for highly effective cancer therapy.
基金funded by the National Natural Science Foundation of China(31320103918 and 82104318)Key Research and Development Program of Jiangsu Province(BE2021644)+4 种基金the Jiangsu Innovative and Entrepreneurial Talent Programme(JSSCBS20211568)the Science and Technology Plan of Suzhou(SKJYD2021161 and SKY2022046)Key Project of Jiangsu Provincial Health Commission(zd2021050)the Project of State Key Laboratory of Radiation Medicine and Protection,Soochow University(GZK1202203)support of Jiangsu Institute of Nuclear Medicine for the ^(89)Zr-PET imaging in this study。
文摘B7 homolog 3(B7-H3)has attracted much attention in glioblastoma(GBM)radioimmunotherapy(RIT)due to its abnormally high expression on tumor cells.In this study,we report that two specific humanized anti-human B7-H3 antibodies(hu4G4 and hu4H12)derived from mouse anti-human B7-H3 antibodies that were generated by computer-aided design and exclusively recognize membrane expression of B7-H3 by human glioma cells,Hu4G4 and hu4H12 were radiolabeled with^(89)Zr for RIT antibody screening.Micro-positron emission tomography(PET)imaging,biodistribution and pharmacokinetic(PK)analyses of^(89)Zr-labeled antibodies were performed in U87-xenografted models.^(125)I labelling of the antibodies for single-photon emission computed tomography(SPECT)imaging was also used to investigate the biological behavior of the antibodies in vivo.Fu rthermore,the pharmacodynamic(PD)of the^(131)Ilabeled antibodies were evaluated in U87-xenografted mice and GL261 Red-FLuc-B7-H3 in situ glioma tumor models.Micro-PET imaging and biodistribution analysis with a gamma counter showed that^(89)Zr-deferoxamine(DFO)-hu4G4 had higher tumor targeting performance with lower liver uptake than^(89)Zr-DFO-(hu4H12,immunoglobulin G(IgG)).The biodistribution results of^(125)I-SPECT imaging were similar to those of^(89)Zr-PET imaging,though the biodistribution in long bone joints and the thyroid varied.The PD analysis results indicated that^(131)I-hu4G4 had an excellent therapeutic effect and high safety with no apparent toxicity.Interestingly,^(131)I-hu4G4 improved the tumor vasculature in tissues with higher expression of collagen typeⅣand platelet-derived growth factor receptorβ(PDGFR-β)compared with control treatment,as determined by immunofluorescence(IF),which contributed to inhibiting tumor growth.Taken together,our data indicate that hu4G4 exhibits good tumor targeting and specificity,achieves low nonspecific concentrations in normal tissues,and has acceptable PK characteristics.^(131)I-hu4G4 also exerts effective antitumor effects with an ideal safety profile.Therefore,we expect hu4G4 to be an excellent antibody for the development of GBM RIT.
基金supported by the National Natural Science Foundation of China(Nos.U24A20765 and T2321005)Jiangsu Provincial Science and Technology Plan Special Fund(No.BM2023003)+1 种基金Jiangsu Provincial Medical Key Discipline(No.ZDXK202247)the Priority Academic Program Development of the Jiangsu Higher Education Institutes.
文摘Cancer vaccine efficacy relies on T cells eliciting tumor-specific adaptive immunity,with antigen-presenting cells,particularly dendritic cells(DCs),playing a crucial role.After capturing antigens,DCs migrate to lymph nodes,where they present antigens to naïve T cells and activate B and natural killer(NK)cells,thereby strengthening anti-tumor immune responses.However,limitations in immune adjuvants and insufficient antigen presentation hinder DCs migration,reducing vaccine effectiveness.This study introduces an outer membrane vesicle(OMV)-based platform engineered to express Vibrio vulnificus flagellin B(FlaB),a Toll-like receptor 5(TLR5)agonist.FlaB effectively activates DCs,enhances interactions with T cells,provides robust costimulatory signals,and promotes cytotoxic CD8^(+)T cell differentiation.Compared to unmodified OMV-Ag,the antigen-loaded OMV-FlaB-Ag nanovaccine significantly enhances DC function,eliciting potent antitumor responses and delaying tumor progression across multiple models.When combined with immune checkpoint inhibitors,it further amplifies antitumor immunity,markedly suppressing tumor growth and improving therapeutic outcomes.
