Head and neck cancer is a significant threat to human health and is charac-terized by high 5-year morbidity and mortality rates.Addressing this challenge requires the application of precision medicine,but the inherent...Head and neck cancer is a significant threat to human health and is charac-terized by high 5-year morbidity and mortality rates.Addressing this challenge requires the application of precision medicine,but the inherent heterogeneity of head and neck cancer complicates its treatment.Radiogenomics,an inter-disciplinary field at the intersection of genomics and radiology,may represent a solution.Radiogenomics offers the potential to revolutionize the diagnosis and treatment of this complex and diverse disease.By comprehensively analyzing the genetic information and radiological features of tumors,clini-cians can gain a profound understanding of patients'conditions.Gaining such in-depth insight facilitates early detection and implementation of personalized treatment strategies,both of which are integral components of precision medicine.Tailored treatments,including surgical interventions and targeted therapies,provide improved outcomes and reduced side effects.Radio-genomics represents a groundbreaking advancement that has the potential to significantly enhance the quality of care and outcomes of patients with head and neck cancer.To shed light on this transformative approach,we performed a comprehensive overview of radiomics and radiogenomics-based diagnostic methods tailored to the unique characteristics of head and neck cancer.展开更多
In the ever-evolving landscape of cancer research and treatment,the quest for novel and non-invasive imaging techniques has become crucial for accurate diagnosis and effective therapy.This study[1]successfully develop...In the ever-evolving landscape of cancer research and treatment,the quest for novel and non-invasive imaging techniques has become crucial for accurate diagnosis and effective therapy.This study[1]successfully developed a good manufacturing practices(GMP)grade ^(89)Zr-labeled anti-Claudin18.2(CLDN18.2)recombinant humanized antibody TST001.^(89)Zr-DFO-TST001 exhibited high radiochemical purity(>99%)and specific activity(24.15±1.34 GBq/mmol).It demonstrated good specificity and rapid tumor accumulation in vivo and in vivo.Through immuno-PET imaging,it enables non-invasive visualization and quantification of CLDN18.2 expression level in CLDN18.2-positive gastrointestinal tumor models.展开更多
1.Introduction Cancer continues to be a major cause of global mortality rates,with conventional treatments such as chemotherapy and radiotherapy exhibiting inconsistent efficacy,high costs,and considerable side effect...1.Introduction Cancer continues to be a major cause of global mortality rates,with conventional treatments such as chemotherapy and radiotherapy exhibiting inconsistent efficacy,high costs,and considerable side effects.Over the past decade,a promising alternative has emerged:cancer immunotherapy,which leverages the body's immune system to identify and eradicate cancer cells[1].展开更多
Tumor hypoxia diminishes the effectiveness of traditional type II photodynamic therapy(PDT)due to oxygen consumption.Type I PDT,which can operate independently of oxygen,is a viable option for treating hypoxic tumors....Tumor hypoxia diminishes the effectiveness of traditional type II photodynamic therapy(PDT)due to oxygen consumption.Type I PDT,which can operate independently of oxygen,is a viable option for treating hypoxic tumors.In this study,we have designed and synthesized JSK@PEG-IR820 NPs that are responsive to the tumor microenvironment(TME)to enhance type I PDT through glutathione(GSH)depletion.Our approach aims to expand the sources of therapeutic benefits by promoting the generation of superoxide radicals(O_(2)^(-).)while minimizing their consumption.The diisopropyl group within PEG-IR820 serves a dual purpose:it functions as a pH sensor for the disassembly of the NPs to release JSK and enhances intermolecular electron transfer to IR820,facilitating efficient O_(2)^(-).generation.Simultaneously,the release of JSK leads to GSH depletion,resulting in the generation of nitric oxide(NO).This,in turn,contributes to the formation of highly cytotoxic peroxynitrite(ONOO^(-).),thereby enhancing the therapeutic efficacy of these NPs.NIR-II fluorescence imaging guided therapy has achieved successful tumor eradication with the assistance of laser therapy.展开更多
Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy.Targeted radionuclide therapy delivers radiation directly to tumor sites.LNC1004 is a fibroblast activation ...Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy.Targeted radionuclide therapy delivers radiation directly to tumor sites.LNC1004 is a fibroblast activation protein(FAP)-targeting radiopharmaceutical,conjugated with the albumin binder Evans Blue,which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies.Herein,we demonstrate that^(68)Ga/^(177)Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts.Radionuclide therapy with^(177)Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells.The combination of^(177)Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice,with mice showing 100%tumor rejection upon rechallenge.Immunohistochemistry,single-cell RNA sequencing(scRNA-seq),and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication,CD8^(+)T-cell activation and expansion,M1 macrophage counts,antitumor activity of neutrophils,and T-cell receptor diversity.A preliminary clinical study demonstrated that^(177)Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers.Further,scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment.This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation.In conclusion,our data supported the efficacy of immunotherapy combined with^(177)Lu-LNC1004 for cancer patients with FAP-positive tumors.展开更多
Gas therapy is emerging as a highly promising therapeutic strategy for cancer treatment.However,there are limitations,including the lack of targeted subcellular organelle accuracy and spatiotemporal release precision,...Gas therapy is emerging as a highly promising therapeutic strategy for cancer treatment.However,there are limitations,including the lack of targeted subcellular organelle accuracy and spatiotemporal release precision,associated with gas therapy.In this study,we developed a series of photoactivatable nitric oxide(NO)donors NRh-R-NO(R=Me,Et,Bn,iPr,and Ph)based on an N-nitrosated upconversion luminescent rhodamine scaffold.Under the irradiation of 808 nm light,only NRh-Ph-NO could effectively release NO and NRh-Ph with a significant turn-on frequency upconversion luminescence(FUCL)signal at 740 nm,ascribed to lower N-N bond dissociation energy.We also investigated the involved multistage near-infrared-controlled cascade release of gas therapy,including the NO released from NRh-Ph-NO along with one NRh-Ph molecule generation,the superoxide anion O_(2)^(⋅−)produced by the photodynamic therapy(PDT)effect of NRh-Ph,and highly toxic peroxynitrite anion(ONOO‒)generated from the co-existence of NO and O_(2)^(⋅−).After mild nano-modification,the nanogenerator(NRh-Ph-NO NPs)empowered with superior biocompatibility could target mitochondria.Under an 808 nm laser irradiation,NRh-Ph-NO NPs could induce NO/ROS to generate RNS,causing a decrease in the mitochondrial membrane potential and initiating apoptosis by caspase-3 activation,which further induced tumor immunogenic cell death(ICD).In vivo therapeutic results of NRh-Ph-NO NPs showed augmented RNS-potentiated gas therapy,demonstrating excellent biocompatibility and effective tumor inhibition guided by real-time FUCL imaging.Collectively,this versatile strategy defines the targeted RNS-mediated cancer therapy.展开更多
The blockade of cytoprotective autophagy has been demonstrated to effectively enhance the efficacy of sonodynamic therapy(SDT).However,the limited recognition of antiautophagy agents for autophagosomes impedes the cli...The blockade of cytoprotective autophagy has been demonstrated to effectively enhance the efficacy of sonodynamic therapy(SDT).However,the limited recognition of antiautophagy agents for autophagosomes impedes the clinical application of autophagy inhibition.To efficiently deliver hydroxychloroquine(HCQ),an autophagy inhibitor,to autophagosomes,we utilized a strategy based on in situ click chemistry between sulfhydryl(-SH)and maleimide(Mal)groups to trigger autophagosomes tracking and suppress tumor growth synergistically.A cascade nanoreactor was synthesized by encapsulating Mal-modified HCQ(MHCQ)into a manganese porphyrin-based metal-organic framework with sonosensitizer properties,followed by poly(ethylene glycol)ylated liposomal membrane coating.After ultrasound irradiation,SDT-induced apoptotic cells released damaged proteins with free-SH groups,which MHCQ rapidly captured in situ via a Malthiol click reaction.When autophagosomes actively wrapped damaged proteins for detoxification,they simultaneously internalized HCQ anchored on proteins.In this scenario,antiautophagy drugs could actively track intracellular autophagosomes instead of undergoing passive diffusion in the cytosol.The interaction between HCQ and autophagic vesicles was greatly enhanced,which strengthened the blocking efficiency of autophagy and resulted in complete cell death.Overall,this study with smart design provides a promising strategy for improving intracellular targeted delivery to autophagosomes,thereby enhancing antitumor therapy.展开更多
Abnormal metabolism has become a potential target for highly malignant and invasive triple-negative breast cancer(TNBC)due to its relatively low response to traditional therapeutics.The existing metabolic intervention...Abnormal metabolism has become a potential target for highly malignant and invasive triple-negative breast cancer(TNBC)due to its relatively low response to traditional therapeutics.The existing metabolic interventions demonstrated unsatisfactory therapeutic outcomes and potential systemic toxicity,resulting from the metabolic instability and limited targeting ability of inhibitors as well as complex tumor microenvironment.To address these limitations,here we developed a robust pyroelectric BaTiO_(3)@Au core–shell nanostructure(BTO@Au)to selectively and persistently block energy generation of tumor cells.Stimulated by near-infrared(NIR)laser,the Au shell could generate heat to activate the BaTiO_(3)core to produce reactive oxygen species(ROS)regardless of the constrained microenvironment,thus prominently inhibits mitochondrial oxidative phosphorylation(OXPHOS)and reduces ATP production to induce TNBC cell apoptosis.The therapeutic effects have been well demonstrated in vitro and in vivo,paving a new way for the development of metabolic interventions.展开更多
Peptide receptor radionuclide therapy(PRRT)with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors(NETs).Previous studies have sh...Peptide receptor radionuclide therapy(PRRT)with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors(NETs).Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue(denoted as^(177)Lu-EB-TATE)is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs.This study aimed to enhance the in vivo stability,pharmacokinetics,and pharmacodynamics of^(177)Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain,resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical,^(177)Lu-LNC1010,for PRRT.In preclinical studies,^(177)Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts.Thereafter,we presented the first-in-human dose escalation study of^(177)Lu-LNC1010 in patients with advanced/metastatic NETs.^(177)Lu-LNC1010 was well-tolerated by all patients,with minor adverse effects,and exhibited significant uptake and prolonged retention in tumor lesions,with higher tumor radiation doses than those of^(177)Lu-EB-TATE.Preliminary PRRT efficacy results showed an 83%disease control rate and a 42%overall response rate after two^(177)Lu-LNC1010 treatment cycles.These encouraging findings warrant further investigations through multicenter,prospective,and randomized controlled trials.展开更多
基金National University of Singapore,Grant/Award Number:NUHSRO/2022/005/Startup/02NSFC,Grant/Award Number:82202231。
文摘Head and neck cancer is a significant threat to human health and is charac-terized by high 5-year morbidity and mortality rates.Addressing this challenge requires the application of precision medicine,but the inherent heterogeneity of head and neck cancer complicates its treatment.Radiogenomics,an inter-disciplinary field at the intersection of genomics and radiology,may represent a solution.Radiogenomics offers the potential to revolutionize the diagnosis and treatment of this complex and diverse disease.By comprehensively analyzing the genetic information and radiological features of tumors,clini-cians can gain a profound understanding of patients'conditions.Gaining such in-depth insight facilitates early detection and implementation of personalized treatment strategies,both of which are integral components of precision medicine.Tailored treatments,including surgical interventions and targeted therapies,provide improved outcomes and reduced side effects.Radio-genomics represents a groundbreaking advancement that has the potential to significantly enhance the quality of care and outcomes of patients with head and neck cancer.To shed light on this transformative approach,we performed a comprehensive overview of radiomics and radiogenomics-based diagnostic methods tailored to the unique characteristics of head and neck cancer.
基金supported by the National University of Singapore(Grant Nos.:NUHSRO/2021/097/Startup/13,NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUSMed/TCE/LOA,NUHSRO/2021/034/TRP/09/Nanomedicine,and NUHSRO/2021/044/Kickstart/09/LOA)National Medical Research Council(Grant Nos.:OFYIRG23jan-0025,OFYIRG23jan-0017,MOH-001254-01,and CG21APR1005)+2 种基金Singapore Ministry of Education Academic Research Fund(Grant Nos.:NUHSRO/2022/093/T1/Seed-Sep/06 and MOE-000387-01)National Research Foundation(Grant No.:CRP28-2022RS-0001),National Natural Science Foundation of China(Grant No.:82202206)Beijing Natural Science Foundation(Grant No.:7224365).
文摘In the ever-evolving landscape of cancer research and treatment,the quest for novel and non-invasive imaging techniques has become crucial for accurate diagnosis and effective therapy.This study[1]successfully developed a good manufacturing practices(GMP)grade ^(89)Zr-labeled anti-Claudin18.2(CLDN18.2)recombinant humanized antibody TST001.^(89)Zr-DFO-TST001 exhibited high radiochemical purity(>99%)and specific activity(24.15±1.34 GBq/mmol).It demonstrated good specificity and rapid tumor accumulation in vivo and in vivo.Through immuno-PET imaging,it enables non-invasive visualization and quantification of CLDN18.2 expression level in CLDN18.2-positive gastrointestinal tumor models.
基金supported by Australian Centre for AI in Medical Innovation(ACAMI)funded by the Victoria State Government,National University of Singapore(NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUSMed/TCE/LOA,NUHSRO/2021/034/TRP/09/Nanomedicine,NUHSRO/2021/044/Kickstart/09/LOA,and 230173-A0001)National Medical Research Council(MOH-001388-00,CG21APR1005,MOH-001500-00,and MOH-001609-00)+1 种基金Singapore Ministry of Education(MOE-000387-00 and MOET32023-0005)National Research Foundation(NRF-000352-00)。
文摘1.Introduction Cancer continues to be a major cause of global mortality rates,with conventional treatments such as chemotherapy and radiotherapy exhibiting inconsistent efficacy,high costs,and considerable side effects.Over the past decade,a promising alternative has emerged:cancer immunotherapy,which leverages the body's immune system to identify and eradicate cancer cells[1].
基金the National University of Singapore(NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUSMed/TCE/LOA,NUHSRO/2021/034/TRP/09/Nanomedicine)National Medical Research Council(MOH-001388-00,MOH-001041,CG21APR1005)+2 种基金Singapore Ministry of Education(MOE-000387-00)National Research Foundation(NRF-000352-00)the Open Fund Young Individual Research Grant of Singapore(MOH-001127-01).
文摘Tumor hypoxia diminishes the effectiveness of traditional type II photodynamic therapy(PDT)due to oxygen consumption.Type I PDT,which can operate independently of oxygen,is a viable option for treating hypoxic tumors.In this study,we have designed and synthesized JSK@PEG-IR820 NPs that are responsive to the tumor microenvironment(TME)to enhance type I PDT through glutathione(GSH)depletion.Our approach aims to expand the sources of therapeutic benefits by promoting the generation of superoxide radicals(O_(2)^(-).)while minimizing their consumption.The diisopropyl group within PEG-IR820 serves a dual purpose:it functions as a pH sensor for the disassembly of the NPs to release JSK and enhances intermolecular electron transfer to IR820,facilitating efficient O_(2)^(-).generation.Simultaneously,the release of JSK leads to GSH depletion,resulting in the generation of nitric oxide(NO).This,in turn,contributes to the formation of highly cytotoxic peroxynitrite(ONOO^(-).),thereby enhancing the therapeutic efficacy of these NPs.NIR-II fluorescence imaging guided therapy has achieved successful tumor eradication with the assistance of laser therapy.
基金funded by the National Natural Science Foundation of China(82071961,82272037)Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare,Key Scientific Research Program for Young Scholars in Fujian(2021ZQNZD016)+6 种基金Fujian Natural Science Foundation for Distinguished Young Scholars(2022D005)Key Medical and Health Projects in Xiamen(grant number 3502Z20209002)Xiamen Key Laboratory of Radiation Oncology,Xiamen Clinical Research Center for Head and Neck Cancer,and 2021 National Clinical Key Specialty,(Oncology,grant number 3210013)The National University of Singapore(NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUSMed/TCE/LOA,NUHSRO/2021/034/TRP/09/Nanomedicine)National Medical Research Council(MOH-001388-00,CG21APR1005)Singapore Ministry of Education(MOE-000387-00)National Research Foundation(NRF-000352-00).
文摘Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy.Targeted radionuclide therapy delivers radiation directly to tumor sites.LNC1004 is a fibroblast activation protein(FAP)-targeting radiopharmaceutical,conjugated with the albumin binder Evans Blue,which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies.Herein,we demonstrate that^(68)Ga/^(177)Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts.Radionuclide therapy with^(177)Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells.The combination of^(177)Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice,with mice showing 100%tumor rejection upon rechallenge.Immunohistochemistry,single-cell RNA sequencing(scRNA-seq),and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication,CD8^(+)T-cell activation and expansion,M1 macrophage counts,antitumor activity of neutrophils,and T-cell receptor diversity.A preliminary clinical study demonstrated that^(177)Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers.Further,scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment.This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation.In conclusion,our data supported the efficacy of immunotherapy combined with^(177)Lu-LNC1004 for cancer patients with FAP-positive tumors.
基金This work was financially supported by the National Natural Science Foundation of China(82272148,China)the“Double First-Class”University Project(CPUQNJC22-03,China)+4 种基金the Jiangsu Funding Program for Excellent Postdoctoral Talent(2022ZB301,China)the National University of Singapore(NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUSMed/TCE/LOA,NUHSRO/2021/034/TRP/09/Nanomedicine)National Medical Research Council(MOH-OFIRG23jan-0005,CG21APR1005)Singapore Ministry of Education(MOE-000387-00)National Research Foundation(NRF-000352-00).
文摘Gas therapy is emerging as a highly promising therapeutic strategy for cancer treatment.However,there are limitations,including the lack of targeted subcellular organelle accuracy and spatiotemporal release precision,associated with gas therapy.In this study,we developed a series of photoactivatable nitric oxide(NO)donors NRh-R-NO(R=Me,Et,Bn,iPr,and Ph)based on an N-nitrosated upconversion luminescent rhodamine scaffold.Under the irradiation of 808 nm light,only NRh-Ph-NO could effectively release NO and NRh-Ph with a significant turn-on frequency upconversion luminescence(FUCL)signal at 740 nm,ascribed to lower N-N bond dissociation energy.We also investigated the involved multistage near-infrared-controlled cascade release of gas therapy,including the NO released from NRh-Ph-NO along with one NRh-Ph molecule generation,the superoxide anion O_(2)^(⋅−)produced by the photodynamic therapy(PDT)effect of NRh-Ph,and highly toxic peroxynitrite anion(ONOO‒)generated from the co-existence of NO and O_(2)^(⋅−).After mild nano-modification,the nanogenerator(NRh-Ph-NO NPs)empowered with superior biocompatibility could target mitochondria.Under an 808 nm laser irradiation,NRh-Ph-NO NPs could induce NO/ROS to generate RNS,causing a decrease in the mitochondrial membrane potential and initiating apoptosis by caspase-3 activation,which further induced tumor immunogenic cell death(ICD).In vivo therapeutic results of NRh-Ph-NO NPs showed augmented RNS-potentiated gas therapy,demonstrating excellent biocompatibility and effective tumor inhibition guided by real-time FUCL imaging.Collectively,this versatile strategy defines the targeted RNS-mediated cancer therapy.
基金China Postdoctoral Science Foundation,Grant/Award Numbers:2022TQ0396,2023MD744153National Natural Science Foundation of China,Grant/Award Numbers:82302218,82171946+2 种基金CQMU Program for Youth Innovation in Future Medicine,Grant/Award Number:W0026Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University,Grant/Award Number:KR2023Y044Chongqing Science and Health Joint Medical Research Project-Young and Middle-Aged High-Level Talent Project,Grant/Award Number:2020GDRC011。
文摘The blockade of cytoprotective autophagy has been demonstrated to effectively enhance the efficacy of sonodynamic therapy(SDT).However,the limited recognition of antiautophagy agents for autophagosomes impedes the clinical application of autophagy inhibition.To efficiently deliver hydroxychloroquine(HCQ),an autophagy inhibitor,to autophagosomes,we utilized a strategy based on in situ click chemistry between sulfhydryl(-SH)and maleimide(Mal)groups to trigger autophagosomes tracking and suppress tumor growth synergistically.A cascade nanoreactor was synthesized by encapsulating Mal-modified HCQ(MHCQ)into a manganese porphyrin-based metal-organic framework with sonosensitizer properties,followed by poly(ethylene glycol)ylated liposomal membrane coating.After ultrasound irradiation,SDT-induced apoptotic cells released damaged proteins with free-SH groups,which MHCQ rapidly captured in situ via a Malthiol click reaction.When autophagosomes actively wrapped damaged proteins for detoxification,they simultaneously internalized HCQ anchored on proteins.In this scenario,antiautophagy drugs could actively track intracellular autophagosomes instead of undergoing passive diffusion in the cytosol.The interaction between HCQ and autophagic vesicles was greatly enhanced,which strengthened the blocking efficiency of autophagy and resulted in complete cell death.Overall,this study with smart design provides a promising strategy for improving intracellular targeted delivery to autophagosomes,thereby enhancing antitumor therapy.
基金supported by the National Natural Science Foundation of China(Nos.22007063 and 82002063)Shanxi Medical Key Science and Technology Project Plan of China(No.2020XM01)+4 种基金the National University of Singapore Start-up Grant(No.NUHSRO/2020/133/Startup/08)NUS School of Medicine Nanomedicine Translational Research Program(No.NUHSRO/2021/034/TRP/09/Nanomedicine)the Science Research Start-up Fund for Doctor of Shanxi Province(No.XD1809 and XD2011)the Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi(No.2019L0414)Shanxi Province Science Foundation for Youths(No.201901D211316).
文摘Abnormal metabolism has become a potential target for highly malignant and invasive triple-negative breast cancer(TNBC)due to its relatively low response to traditional therapeutics.The existing metabolic interventions demonstrated unsatisfactory therapeutic outcomes and potential systemic toxicity,resulting from the metabolic instability and limited targeting ability of inhibitors as well as complex tumor microenvironment.To address these limitations,here we developed a robust pyroelectric BaTiO_(3)@Au core–shell nanostructure(BTO@Au)to selectively and persistently block energy generation of tumor cells.Stimulated by near-infrared(NIR)laser,the Au shell could generate heat to activate the BaTiO_(3)core to produce reactive oxygen species(ROS)regardless of the constrained microenvironment,thus prominently inhibits mitochondrial oxidative phosphorylation(OXPHOS)and reduces ATP production to induce TNBC cell apoptosis.The therapeutic effects have been well demonstrated in vitro and in vivo,paving a new way for the development of metabolic interventions.
基金supported by the National Natural Science Foundation of China(No.82071961)Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare,Key Scientific Research Program for Yong Scholars in Fujian(No.2021ZQNZD016,China)+5 种基金Fujian Natural Science Foundation for Distinguished Young Scholars(No.2022D005,China)Innovation of Science and Technology,Fujian Province(No.2021Y9134,China)National University of Singapore(No.NUHSRO/2020/133/Startup/08,NUHSRO/2023/008/NUSMed/TCE/LOA,NUHSRO/2021/034/TRP/09/Nanomedicine)National Medical Research Council(No.MOH-001388-00,MOH-001041,CG21APR1005,Singapore)Singapore Ministry of Education(No.MOE-000387-00,Singapore)National Research Foundation(No.NRF-000352-00,Singapore).
文摘Peptide receptor radionuclide therapy(PRRT)with radiolabeled SSTR2 agonists is a treatment option that is highly effective in controlling metastatic and progressive neuroendocrine tumors(NETs).Previous studies have shown that an SSTR2 agonist combined with albumin binding moiety Evans blue(denoted as^(177)Lu-EB-TATE)is characterized by a higher tumor uptake and residence time in preclinical models and in patients with metastatic NETs.This study aimed to enhance the in vivo stability,pharmacokinetics,and pharmacodynamics of^(177)Lu-EB-TATE by replacing the maleimide-thiol group with a polyethylene glycol chain,resulting in a novel EB conjugated SSTR2-targeting radiopharmaceutical,^(177)Lu-LNC1010,for PRRT.In preclinical studies,^(177)Lu-LNC1010 exhibited good stability and SSTR2-binding affinity in AR42J tumor cells and enhanced uptake and prolonged retention in AR42J tumor xenografts.Thereafter,we presented the first-in-human dose escalation study of^(177)Lu-LNC1010 in patients with advanced/metastatic NETs.^(177)Lu-LNC1010 was well-tolerated by all patients,with minor adverse effects,and exhibited significant uptake and prolonged retention in tumor lesions,with higher tumor radiation doses than those of^(177)Lu-EB-TATE.Preliminary PRRT efficacy results showed an 83%disease control rate and a 42%overall response rate after two^(177)Lu-LNC1010 treatment cycles.These encouraging findings warrant further investigations through multicenter,prospective,and randomized controlled trials.
