Abstract 11287: Translation of an Anti-Inflammatory Nanomedical Treatment for Atherosclerosis: First Randomized Clinical Trial in Patients With Cardiovascular Disease
Introduction: Anti-inflammatory therapeutics for atherosclerosis are lacking predominantly due to fear of immunosuppressive side effects. Nanomedicine holds promise to overcome this hurdle, via selectively targeting atherosclerosis. Here we present a program aimed at translating a nanomedicine-based strategy for cardiovascular patients.
Methods: preclinical: Pharmacokinetics and safety of PEGylated liposomal nanoparticle containing prednisolone (LN-PLP) was assessed in rats and rabbits. Efficacy of LN-PLP was evaluated in atherosclerosis rabbit model using dynamic contrast enhanced MRI (DCE-MRI) and positron emission tomography (PET) as readout for arterial wall permeability and inflammation. clinical: Local delivery was evaluated by infusing patients with LN-PLP (3mg/kg) 7 and 3 days prior to vascular surgery (n=7). Double staining for CD68 (macrophage) and PEG (LN-PLP) was performed on macrophages isolated from excised plaque tissue. In a randomized controlled trial, efficacy was evaluated by infusing LN-PLP (3mg/kg at day 1 and 7) or placebo in cardiovascular patients (n=30) using PET (target to background ratio, TBR) and DCE-MRI (Ktrans) as readout.
Results: Bio-availability improved via liposomal encapsulation of prednisolone (t½ 39.8hr LN-PLP vs <0.1hr prednisolone, p<0.01). In atherosclerotic rabbits (n=20), a single dose of LN-PLP (10mg/kg) significantly reduced both arterial wall permeability (p=0.01) as inflammatory activity (p=0.02), comparing LN-PLP vs placebo. In plaque macrophages 77% was positive for double-staining PEG (green) and CD68 (red), demonstrating successful delivery of LN-PLP to human plaques. In cardiovascular patients, LN-PLP resulted in a 9% increase in carotid TBR (p=0.01), and a 60% increase in carotid Ktrans (p=0.01), both with no change in placebo group.
Conclusion: LN-PLP shows favorable bio-availability and anti-inflammatory effects in preclinical models. Notwithstanding local delivery of LN-PLP into plaque macrophages in humans, LN-PLP does not decrease arterial wall permeability and inflammation. This successful delivery platform will serve to evaluate other compounds as targeted anti-atherosclerotic strategies.
- Cardiovascular disease
- Immunosuppressive therapy
- Cardiovascular imaging
- Interventional studies
- © 2013 by American Heart Association, Inc.