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Published on: November 17, 2017
HDL mimetic CER-001 targets atherosclerotic plaques in patients
Kang He Zheng1, Fleur M van der Valk1, Loek P Smits1
1Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Insights
High-density lipoprotein (HDL) mimetic CER-001 effectively targets atherosclerotic plaques in patients, increasing apoA-I levels and cholesterol efflux. This study demonstrates CER-001
Area of Science:
- Cardiovascular Research
- Nanomedicine
- Biotechnology
Background:
- High-density lipoprotein (HDL) mimetics show variable results in reducing atherosclerosis.
- Limited delivery of HDL mimetics to atherosclerotic lesions may explain suboptimal outcomes.
- Recombinant apolipoprotein A-I (apoA-I) based HDL mimetics are being investigated for improved therapeutic delivery.
Purpose of the Study:
- To evaluate the targeted delivery of CER-001, an HDL mimetic containing recombinant human apoA-I, to carotid atherosclerotic plaques.
- To assess the impact of CER-001 infusion on plasma apoA-I levels and cholesterol efflux capacity.
- To correlate CER-001 uptake in plaques with imaging markers of plaque activity.
Main Methods:
- CER-001 was radiolabeled with zirconium-89 ((89)Zr) for PET/CT imaging.
- Eight patients with >50% carotid stenosis received a single infusion of CER-001 co-administered with (89)Zr-CER-001.
- Serial PET/CT and contrast-enhanced MRI (CE-MRI) were used to quantify CER-001 delivery and plaque characteristics.
Main Results:
- CER-001 infusion significantly increased plasma apoA-I levels and cholesterol efflux capacity.
- PET/CT imaging revealed significant arterial uptake of CER-001 in plaques, peaking at 24-48 hours post-infusion.
- Uptake (target-to-background ratio) was higher in plaque segments and correlated with CE-MRI contrast enhancement.
Conclusions:
- CER-001 effectively targets atherosclerotic plaques in patients, as evidenced by PET/CT imaging.
- The study supports the use of HDL mimetics like CER-001 for targeted delivery in atherosclerosis.
- Findings may inform future nanomedicine strategies for atherosclerosis treatment using HDL particles.
Background And Aims:
Infusion of high-density lipoprotein (HDL) mimetics aimed at reducing atherosclerotic burden has led to equivocal results, which may relate in part to the inability of HDL mimetics to adequately reach atherosclerotic lesions in humans. This study evaluated delivery of recombinant human apolipoprotein A-I (apoA-I) containing HDL mimetic CER-001 in carotid plaques in patients.
Methods:
CER-001 was radiolabeled with the long-lived positron emitter zirconium-89 ((89)Zr) to enable positron emission tomography with computed tomography (PET/CT) imaging. Eight patients with atherosclerotic carotid artery disease (>50% stenosis) received a single infusion of unlabeled CER-001 (3 mg/kg), co-administered with 10 mg of (89)Zr-labeled CER-001 (18 MBq). Serial PET/CT imaging and contrast enhanced-magnetic resonance imaging (CE-MRI) were performed to evaluate targeted delivery of CER-001.
Results:
One hour after infusion, mean plasma apoA-I levels increased by 9.9 mg/dL (p = 0.026), with a concomitant relative increase in the plasma cholesterol efflux capacity of 13.8% (p < 0.001). Using serial PET/CT imaging, we showed that arterial uptake of CER-001 expressed as target-to-background ratio (TBRmax) increased significantly 24 h after infusion, and remained increased up to 48 h (TBRmax t = 10 min: 0.98; t = 24 h: 1.14 (p = 0.001); t = 48 h: 1.12 (p = 0.007)). TBRmax was higher in plaque compared with non-plaque segments (1.18 vs. 1.05; p < 0.001). Plaque TBRmax correlated with local plaque contrast enhancement (r = 0.56; p = 0.019) as assessed by CE-MRI.
Conclusions:
Infusion of HDL mimetic CER-001 increases plasma apoA-I concentration and plasma cholesterol efflux capacity. Our data support the concept that CER-001 targets plaque regions in patients, which correlates with plaque contrast enhancement. These clinical findings may also guide future nanomedicine development using HDL particles for drug delivery in atherosclerosis.
Clinical Trial Registration:
Netherlands Trial Registry - NTR5178. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5178.
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