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Painting blood vessels and atherosclerotic plaques with an adhesive drug depot.

ABSTRACT: The treatment of diseased vasculature remains challenging, in part because of the difficulty in implanting drug-eluting devices without subjecting vessels to damaging mechanical forces. Implanting materials using adhesive forces could overcome this challenge, but materials have previously not been shown to durably adhere to intact endothelium under blood flow. Marine mussels secrete strong underwater adhesives that have been mimicked in synthetic systems. Here we develop a drug-eluting bioadhesive gel that can be locally and durably glued onto the inside surface of blood vessels. In a mouse model of atherosclerosis, inflamed plaques treated with steroid-eluting adhesive gels had reduced macrophage content and developed protective fibrous caps covering the plaque core. Treatment also lowered plasma cytokine levels and biomarkers of inflammation in the plaque. The drug-eluting devices developed here provide a general strategy for implanting therapeutics in the vasculature using adhesive forces and could potentially be used to stabilize rupture-prone plaques.

SUBMITTER: Kastrup CJ

PROVIDER: S-EPMC3535589 | biostudies-other | 2012 Dec

REPOSITORIES: biostudies-other

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Painting blood vessels and atherosclerotic plaques with an adhesive drug depot.

Kastrup Christian J CJ Nahrendorf Matthias M Figueiredo Jose Luiz JL Lee Haeshin H Kambhampati Thiruvengadam Swetha S Lee Timothy T Cho Seung-Woo SW Gorbatov Rostic R Iwamoto Yoshiko Y Dang Tram T TT Dutta Partha P Yeon Ju Hun JH Cheng Hao H Pritchard Christopher D CD Vegas Arturo J AJ Siegel Cory D CD MacDougall Samantha S Okonkwo Michael M Thai Anh A Stone James R JR Coury Arthur J AJ Weissleder Ralph R Langer Robert R Anderson Daniel G DG

Proceedings of the National Academy of Sciences of the United States of America 20121211 52

The treatment of diseased vasculature remains challenging, in part because of the difficulty in implanting drug-eluting devices without subjecting vessels to damaging mechanical forces. Implanting materials using adhesive forces could overcome this challenge, but materials have previously not been shown to durably adhere to intact endothelium under blood flow. Marine mussels secrete strong underwater adhesives that have been mimicked in synthetic systems. Here we develop a drug-eluting bioadhesi ...[more]

PMID: 23236189

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Project description:BackgroundGrowth differentiation factor (GDF)-15 is linked to inflammation, cancer, and atherosclerosis. GDF-15 is expressed in most tissues but is extremely induced under pathological conditions. Elevated serum levels are suggested as a risk factor and a marker for cardiovascular diseases. However, the cellular sources and the effects of GDF-15 on the cardiovascular system have not been completely elucidated including progression, and morphology of atherosclerotic plaques. Thus, this work aimed to characterize the influence of GDF-15 deficiency on the morphology of atherosclerotic plaques in blood vessels with low-oxygen blood and low blood pressure as the pulmonary trunk (PT), in hypercholesterolemic ApoE-/- mice.MethodsGDF-15-/- ApoE-/- mice were generated by crossbreeding of ApoE-/-- and GDF-15-/- mice. After feeding a cholesterol-enriched diet (CED) for 20 weeks, samples of the brachiocephalic trunk (BT) and PT were dissected and lumen stenosis (LS) was measured. Furthermore, changes in the cellularity of the PT, amounts of apoptosis-, autophagy-, inflammation- and proliferation-relevant proteins were immunohisto-morphometrically analyzed. Additionally, we examined an atherosclerotic plaque in a human post mortem sample of the pulmonary artery.ResultsAfter CED the body weight of GDF-15-/-ApoE-/- was 22.9% higher than ApoE-/-. Double knockout mice showed also an 35.3% increase of plasma triglyceride levels, whereas plasma cholesterol was similar in both genotypes. LS in the BT and PT of GDF-15-/-ApoE-/- mice was significantly reduced by 19.0% and by 6.7% compared to ApoE-/-. Comparing LS in PT and BT of the same genotype revealed a significant 38.8% (ApoE-/-) or 26.4% (GDF-15-/-ApoE-/-) lower LS in the PT. Immunohistomorphometry of atherosclerotic lesions in PT of GDF-15-/-ApoE-/- revealed significantly increased levels (39.8% and 7.3%) of CD68 + macrophages (MΦ) and α-actin + smooth muscle cells than in ApoE-/-. The density of TUNEL + , apoptotic cells was significantly (32.9%) higher in plaques of PT of GDF-15-/-ApoE-/- than in ApoE-/-. Analysis of atherosclerotic lesion of a human pulmonary artery showed sm-α-actin, CD68+, TUNEL+, Ki67+, and APG5L/ATG+ cells as observed in PT. COX-2+ and IL-6+ immunoreactivities were predominantly located in endothelial cells and subendothelial space. In BT and PT of GDF15-/-ApoE-/- mice the necrotic area was 10% and 6.5% lower than in ApoE-/-. In BT and PT of GDF15-/-ApoE-/- we found 40% and 57% less unstable plaques than ApoE-/- mice.ConclusionsAtherosclerotic lesions occur in both, BT and PT, however, the size is smaller in PT, possibly due to the effect of the low-oxygen blood and/or lower blood pressure. GDF-15 is involved in atherosclerotic processes in BT and PT, although different mechanisms (e.g. apoptosis) in these two vessels seem to exist.

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Painting blood vessels and atherosclerotic plaques with an adhesive drug depot.

Publications

Painting blood vessels and atherosclerotic plaques with an adhesive drug depot.

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