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
Vulnerable atherosclerotic plaques are responsible for most cardiovascular diseases(CVDs).Folate receptor(FR)positive activated macrophages were thought to be a prominent component in the development of vulnerable pla...Vulnerable atherosclerotic plaques are responsible for most cardiovascular diseases(CVDs).Folate receptor(FR)positive activated macrophages were thought to be a prominent component in the development of vulnerable plaque.The objective of this study is to develop folate conjugated two-dimensional(2D)Pd@Au nanomaterials(Pd@Au-PEG-FA)for targeted multimodal imaging of the FRs in advanced atherosclerotic plaques.Pharmacokinetic and imaging studies(single photon emission computed tomography(SPECT),computed tomography(CT)and photoacoustic(PA)imaging)were performed to confirm the prolonged blood half-life and enrichment of radioactivity in atherosclerotic plaques.Strong signals were detected in vivo with SPECT,CT and PA imaging in heavy atherosclerotic plaques,which were significantly higher than those of the normal aortas after injection of Pd@Au-PEG-FA.Blocking studies with preinjection of excess FA could effectively reduce the targeting ability of Pd@Au-PEG-FA in atherosclerotic plaques,further demonstrating the specific binding of Pd@Au-PEG-FA for plaque lesions.Histopathological characterization revealed that the signal of probe was in accordance with the high-risk plaques.In summary,the Pd@Au-PEG-FA has favorable pharmacokinetic properties and provides a valuable approach for detecting high-risk plaques in the presence of FRs in atherosclerotic plaques.展开更多
Lactic acid(LA)plays a major role in the occurrence,development,and spread of cancer.Enlightened by its high accumulation in tumor site,a novel lactate oxidase(LOD)conjugated two-dimensional Pd@Ir nanoplatform(Pd@Ir-L...Lactic acid(LA)plays a major role in the occurrence,development,and spread of cancer.Enlightened by its high accumulation in tumor site,a novel lactate oxidase(LOD)conjugated two-dimensional Pd@Ir nanoplatform(Pd@Ir-LOD,PIL)was fabricated to combine cascade reaction with photothermal for tumor therapy.In detail,the overexpressed LA in tumor microenvironment(TME)was a key factor to activate the PIL-based cascade reaction:(1)Plenty of H_(2)O_(2)could be generated from LA by the catalysis of LOD with O_(2);(2)potent·OH was produced from H_(2)O_(2)due to the peroxidase(POD)-like activity of PIL;(3)meantime,PIL’s catalase(CAT)-like activity could decompose part H_(2)O_(2)into O_(2)to achieve the purpose of LA cyclic oxidization.Moreover,the reduced glutathione(GSH)scavenging capability of PIL might protect the produced reactive oxygen species(ROS)from being cleared to further improve the cascade therapeutic effect.More importantly,PIL had excellent photothermal conversion efficiency(37.35%)and manifested a surprising temperature rising effect in tumor.Taken together,the decreasing LA concentration,accumulation of high-toxic ROS,the depletion of GSH together with the higher intra-tumoral temperature potently enhanced in vivo antitumor therapy.Therefore,a promising therapeutic tactic based on PIL integrating endogenous LA consumption,chemodynamic therapy(CDT),and photothermal therapy(PTT)has been put forward.展开更多
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.
基金supported by the National Postdoctoral Program for Innovative Talents(No.BX201700142)Postdoctoral Science Foundation of China(No.2018M630732)+3 种基金the National Natural Science Foundation of China(Nos.81901805,21906135,81471707,21705037,and 91539126)Hunan Provincial Natural Science Foundation of China(No.2018JJ3092)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(CIFMS 2016-I2M-1-009)Drug Innovation Major Project(2018ZX09711001-003-011).
文摘Vulnerable atherosclerotic plaques are responsible for most cardiovascular diseases(CVDs).Folate receptor(FR)positive activated macrophages were thought to be a prominent component in the development of vulnerable plaque.The objective of this study is to develop folate conjugated two-dimensional(2D)Pd@Au nanomaterials(Pd@Au-PEG-FA)for targeted multimodal imaging of the FRs in advanced atherosclerotic plaques.Pharmacokinetic and imaging studies(single photon emission computed tomography(SPECT),computed tomography(CT)and photoacoustic(PA)imaging)were performed to confirm the prolonged blood half-life and enrichment of radioactivity in atherosclerotic plaques.Strong signals were detected in vivo with SPECT,CT and PA imaging in heavy atherosclerotic plaques,which were significantly higher than those of the normal aortas after injection of Pd@Au-PEG-FA.Blocking studies with preinjection of excess FA could effectively reduce the targeting ability of Pd@Au-PEG-FA in atherosclerotic plaques,further demonstrating the specific binding of Pd@Au-PEG-FA for plaque lesions.Histopathological characterization revealed that the signal of probe was in accordance with the high-risk plaques.In summary,the Pd@Au-PEG-FA has favorable pharmacokinetic properties and provides a valuable approach for detecting high-risk plaques in the presence of FRs in atherosclerotic plaques.
基金supported by the National Natural Science Foundation of China(No.22075233)Natural Science Foundation of Fujian Province(No.2022J01023).
文摘Lactic acid(LA)plays a major role in the occurrence,development,and spread of cancer.Enlightened by its high accumulation in tumor site,a novel lactate oxidase(LOD)conjugated two-dimensional Pd@Ir nanoplatform(Pd@Ir-LOD,PIL)was fabricated to combine cascade reaction with photothermal for tumor therapy.In detail,the overexpressed LA in tumor microenvironment(TME)was a key factor to activate the PIL-based cascade reaction:(1)Plenty of H_(2)O_(2)could be generated from LA by the catalysis of LOD with O_(2);(2)potent·OH was produced from H_(2)O_(2)due to the peroxidase(POD)-like activity of PIL;(3)meantime,PIL’s catalase(CAT)-like activity could decompose part H_(2)O_(2)into O_(2)to achieve the purpose of LA cyclic oxidization.Moreover,the reduced glutathione(GSH)scavenging capability of PIL might protect the produced reactive oxygen species(ROS)from being cleared to further improve the cascade therapeutic effect.More importantly,PIL had excellent photothermal conversion efficiency(37.35%)and manifested a surprising temperature rising effect in tumor.Taken together,the decreasing LA concentration,accumulation of high-toxic ROS,the depletion of GSH together with the higher intra-tumoral temperature potently enhanced in vivo antitumor therapy.Therefore,a promising therapeutic tactic based on PIL integrating endogenous LA consumption,chemodynamic therapy(CDT),and photothermal therapy(PTT)has been put forward.
