Background Antibody-based positron emission tomography(PET)imaging holds great promise for visualizing disease-related proteins in the brain.However,its clinical utility is limited by poor antibody penetration across ...Background Antibody-based positron emission tomography(PET)imaging holds great promise for visualizing disease-related proteins in the brain.However,its clinical utility is limited by poor antibody penetration across the blood–brain barrier(BBB)and the requirement for long-lived radionuclides due to slow antibody pharmacokinetics.Pretargeted imaging strategies,in which antibody administration and radioligand injection are separated in time,enable the use of short-lived,high-resolution PET-compatible radionuclides such as fluorine-18.Methods A bispecific antibody,Bapi-Fab8D3,which targets both amyloid beta(Aβ)and the transferrin receptor(TfR)for TfR-mediated transport across the BBB,was conjugated with trans-cyclooctene(TCO)to enable in vivo click chemistry.Following antibody administration to Alzheimer’s disease(AD)model mice and sufficient time for accumulation at intrabrain Aβdeposits,a fluorine-18-labeled tetrazine was injected to react in vivo with the TCO handles on the antibody.PET imaging,autoradiography,ex vivo quantification,and histological analyses were performed to evaluate the specificity and distribution of the imaging signal.Results Bapi-Fab8D3 retained its binding affinity for both Aβand TfR after TCO-conjugation.In brain sections,reactive TCOs were detected up to three days after antibody injection,indicating successful transcytosis across the BBB and stable target engagement.Pretargeted PET imaging after fluorine-18-labeled tetrazine injection revealed significantly higher signals in AD mice that received TCO-Bapi-Fab8D3 compared to wild-type controls or AD mice that received the unmodified antibody.The uptake pattern corresponded to Aβplaque distribution,and quantitative analysis showed increased signal in AD-relevant brain regions including the hippocampus and thalamus.Conclusions This study demonstrates successful pretargeted PET imaging of brain Aβpathology using a systemically administered bispecific antibody capable of BBB penetration and a fluorine-18-labeled tetrazine.These findings establish a generalizable strategy for high-contrast in vivo imaging of brain protein targets using pretargeted PET,with the potential to expand molecular imaging to protein targets in the brain that are currently inaccessible.展开更多
This work details a newly developed“sandwich”nanoplatform via neutravidin-biotin system for the detection and treatment of inflammation.First,biotinylated-and folate-conjugated optical imaging micelles targeted acti...This work details a newly developed“sandwich”nanoplatform via neutravidin-biotin system for the detection and treatment of inflammation.First,biotinylated-and folate-conjugated optical imaging micelles targeted activated macrophages via folate/folate receptor interactions.Second,multivalent neutravidin proteins in an optimal concentration accumulated on the biotinylated macrophages.Finally,biotinylated anti-inflammatory drug-loaded micelles delivered drugs effectively at the inflammatory sites via a highly specific neutravidin-biotin affinity.Both in vitro and in vivo studies have shown that the“sandwich”pretargeting platform was able to diagnose inflammation by targeting activated macrophages as well as improve the therapeutic efficacy by amplifying the drug delivery to the inflamed tissue.The overall results support that our new pretargeting platform has the potential for inflammatory disease diagnosis and treatment.展开更多
基金Open access funding provided by Uppsala University.Vetenskapsradet(2021-01083,Stina Syvanen,2021–03524,Dag Sehlin)Parkinsonfonden,Alzheimerfonden,Hjarnfonden,Ahlen-stiftelsen,Gun och Bertil Stohnes Stiftelse,Stiftelsen for Gamla Tjanarinnor,Tore Nilsons stiftelse,Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse。
文摘Background Antibody-based positron emission tomography(PET)imaging holds great promise for visualizing disease-related proteins in the brain.However,its clinical utility is limited by poor antibody penetration across the blood–brain barrier(BBB)and the requirement for long-lived radionuclides due to slow antibody pharmacokinetics.Pretargeted imaging strategies,in which antibody administration and radioligand injection are separated in time,enable the use of short-lived,high-resolution PET-compatible radionuclides such as fluorine-18.Methods A bispecific antibody,Bapi-Fab8D3,which targets both amyloid beta(Aβ)and the transferrin receptor(TfR)for TfR-mediated transport across the BBB,was conjugated with trans-cyclooctene(TCO)to enable in vivo click chemistry.Following antibody administration to Alzheimer’s disease(AD)model mice and sufficient time for accumulation at intrabrain Aβdeposits,a fluorine-18-labeled tetrazine was injected to react in vivo with the TCO handles on the antibody.PET imaging,autoradiography,ex vivo quantification,and histological analyses were performed to evaluate the specificity and distribution of the imaging signal.Results Bapi-Fab8D3 retained its binding affinity for both Aβand TfR after TCO-conjugation.In brain sections,reactive TCOs were detected up to three days after antibody injection,indicating successful transcytosis across the BBB and stable target engagement.Pretargeted PET imaging after fluorine-18-labeled tetrazine injection revealed significantly higher signals in AD mice that received TCO-Bapi-Fab8D3 compared to wild-type controls or AD mice that received the unmodified antibody.The uptake pattern corresponded to Aβplaque distribution,and quantitative analysis showed increased signal in AD-relevant brain regions including the hippocampus and thalamus.Conclusions This study demonstrates successful pretargeted PET imaging of brain Aβpathology using a systemically administered bispecific antibody capable of BBB penetration and a fluorine-18-labeled tetrazine.These findings establish a generalizable strategy for high-contrast in vivo imaging of brain protein targets using pretargeted PET,with the potential to expand molecular imaging to protein targets in the brain that are currently inaccessible.
文摘This work details a newly developed“sandwich”nanoplatform via neutravidin-biotin system for the detection and treatment of inflammation.First,biotinylated-and folate-conjugated optical imaging micelles targeted activated macrophages via folate/folate receptor interactions.Second,multivalent neutravidin proteins in an optimal concentration accumulated on the biotinylated macrophages.Finally,biotinylated anti-inflammatory drug-loaded micelles delivered drugs effectively at the inflammatory sites via a highly specific neutravidin-biotin affinity.Both in vitro and in vivo studies have shown that the“sandwich”pretargeting platform was able to diagnose inflammation by targeting activated macrophages as well as improve the therapeutic efficacy by amplifying the drug delivery to the inflamed tissue.The overall results support that our new pretargeting platform has the potential for inflammatory disease diagnosis and treatment.
