Molecular imaging of experimental atherosclerosis using anti-malondialdehyde-modified low-density lipoprotein humanised antibody fragment targeted nanoparticles
| Autor: | A Hartley, M Greene, M Caga-Anan, S Owen, M Mullin, C Pericleous, C Scott, J Mason, D O Haskard, R Khamis |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | European Heart Journal. 43 |
| ISSN: | 1522-9645 0195-668X |
| Popis: | Introduction Oxidative modification of low-density lipoprotein (LDL), for example by malondialdehyde (MDA) adduction with subsequent uptake by macrophages to form foam cells and later the plaque necrotic core, is a key initiating event in atherogenesis. Accordingly, a larger lipid necrotic core is a key plaque vulnerability factor, predisposing plaques to rupture and subsequent thrombosis and development of an acute coronary syndrome. Thus, MDA-LDL is an attractive focus for the molecular targeting of atherosclerotic plaques. Purpose To develop antibody fragment-targeted nanoparticles that can be utilised for both the molecular imaging and therapeutics of vulnerable atherosclerotic plaques. Methods LO1 is an IgG3k natural monoclonal murine antibody that reacts with MDA-LDL. Humanised LO1Fab fragments have been engineered to reduce immunogenicity and improve lesion penetration. These humanised LO1Fab fragments were used to functionalise fluorescent poly(lactic-co-glycolic acid) (PLGA) - polyethylene glycol (PEG) nanoparticles. Nanoparticle in vitro function was assessed, prior to fluorescence molecular tomography (FMT) co-registered with micro-CT, four-hours after iv injection in atherosclerotic LDL-receptor−/− mice fed a high-fat diet for 40-weeks. Results Humanised LO1Fab fragment conjugated fluorescent PLGA-PEG nanoparticles were formulated with 210nm size and polydispersity index (variability of nanoparticle size around the average) of Conclusions Humanised antibody Fab fragment fluorescent nanoparticles have been developed that successfully target MDA-LDL and localise to atherosclerotic plaques in murine experimental atherosclerosis. These targeted nanoparticles have the potential to amplify fluorescent signal for imaging and carry a therapeutic cargo for targeted drug delivery direct to atherosclerotic plaques. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Wellcome Trust Clinical Research Fellowship |
| Databáze: | OpenAIRE |
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