title: Near Infrared Fluorescence (NIRF) Molecular Imaging of Oxidized LDL with an Autoantibody in Experimental Atherosclerosis.
abstract: We aimed to develop a quantitative antibody-based near infrared fluorescence (NIRF) approach for the imaging of oxidized LDL in atherosclerosis. LO1, a well- characterized monoclonal autoantibody that reacts with malondialdehyde-conjugated LDL, was labeled with a NIRF dye to yield LO1-750. LO1-750 specifically identified necrotic core in ex vivo human coronary lesions. Injection of LO1-750 into high fat (HF) fed atherosclerotic Ldlr(-/-) mice led to specific focal localization within the aortic arch and its branches, as detected by fluorescence molecular tomography (FMT) combined with micro-computed tomography (CT). Ex vivo confocal microscopy confirmed LO1-750 subendothelial localization of LO1-750 at sites of atherosclerosis, in the vicinity of macrophages. When compared with a NIRF reporter of MMP activity (MMPSense-645-FAST), both probes produced statistically significant increases in NIRF signal in the Ldlr(-/-) model in relation to duration of HF diet. Upon withdrawing the HF diet, the reduction in oxLDL accumulation, as demonstrated with LO1-750, was less marked than the effect seen on MMP activity. In the rabbit, in vivo injected LO1-750 localization was successfully imaged ex vivo in aortic lesions with a customised intra-arterial NIRF detection catheter. A partially humanized chimeric LO1-Fab-Cys localized similarly to the parent antibody in murine atheroma showing promise for future translation.
authors.affiliation: Vascular Sciences Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Ramzi Y
authors.initials: RY
authors.lastname: Khamis
authors.affiliation: Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Woollard
authors.affiliation: Vascular Sciences Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Gareth D
authors.initials: GD
authors.lastname: Hyde
authors.affiliation: Vascular Sciences Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Boyle
authors.affiliation: Department of Surgery &Cancer, Imperial College London, London, United Kingdom.
authors.forename: Colin
authors.initials: C
authors.lastname: Bicknell
authors.affiliation: Vascular Sciences Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Shang-Hung
authors.initials: SH
authors.lastname: Chang
authors.affiliation: Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Talat H
authors.initials: TH
authors.lastname: Malik
authors.affiliation: Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, USA.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hara
authors.affiliation: Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Mauskapf
authors.affiliation: Biopharm R&D, GlaxoSmithKline, Stevenage, United Kingdom.
authors.forename: David W
authors.initials: DW
authors.lastname: Granger
authors.affiliation: School of Clinical Sciences, University of Bristol, United Kingdom.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Johnson
authors.affiliation: Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, USA.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Ntziachristos
authors.affiliation: Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Matthews
authors.affiliation: Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, USA.
authors.forename: Farouc A
authors.initials: FA
authors.lastname: Jaffer
authors.affiliation: Vascular Sciences Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Dorian O
authors.initials: DO
authors.lastname: Haskard
mesh_terms: D015766:Albendazole; D000818:Animals; D000941:Antigens / Q000276:immunology; D001013:Aorta, Thoracic / Q000000981:diagnostic imaging; D050197:Atherosclerosis / Q000000981:diagnostic imaging / Q000473:pathology*; D001323:Autoantibodies / Q000097:blood / Q000737:chemistry* / Q000276:immunology; D059305:Diet, High-Fat; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007150:Immunohistochemistry; D008077:Lipoproteins, LDL / Q000737:chemistry* / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008315:Malondialdehyde / Q000737:chemistry; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010936:Plant Extracts; D011817:Rabbits; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D055114:X-Ray Microtomography
chemical_list: D000941:Antigens; D001323:Autoantibodies; D005456:Fluorescent Dyes; C000613050:L01-750; D008077:Lipoproteins, LDL; C402832:Lo 701; D010936:Plant Extracts; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D008315:Malondialdehyde; D020782:Matrix Metalloproteinases; D015766:Albendazole