NDLI: In vivo efficacy of HDL-like nanolipid particles containing multivalent peptide mimetics of apolipoprotein A-I.

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In vivo efficacy of HDL-like nanolipid particles containing multivalent peptide mimetics of apolipoprotein A-I.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Zhao, Yannan Black, Audrey S. Bonnet, David J. Maryanoff, Bruce E. Curtiss, Linda K. Leman, Luke J. Ghadiri, M. Reza
Description	Author Affiliation: Zhao Y ( Departments of Chemistry and Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037.); Black AS ( Departments of Chemistry and Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037.); Bonnet DJ ( Departments of Chemistry and Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037.); Maryanoff BE ( Departments of Chemistry and Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037.); Curtiss LK ( Departments of Chemistry and Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037.); Leman LJ ( Departments of Chemistry and Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037.); Ghadiri MR ( Departments of Chemistry and Immunology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037.)
Abstract	We have observed that molecular constructs based on multiple apoA-I mimetic peptides attached to a branched scaffold display promising anti-atherosclerosis functions in vitro. Building on these promising results, we now describe chronic in vivo studies to assess anti-atherosclerotic efficacy of HDL-like nanoparticles assembled from a trimeric construct, administered over 10 weeks either ip or orally to LDL receptor-null mice. When dosed ip, the trimer-based nanolipids markedly reduced plasma LDL-cholesterol levels by 40%, unlike many other apoA-I mimetic peptides, and were substantially atheroprotective. Surprisingly, these nanoparticles were also effective when administered orally at a dose of 75 mg/kg, despite the peptide construct being composed of l-amino acids and being undetectable in the plasma. The orally administered nanoparticles reduced whole aorta lesion areas by 55% and aortic sinus lesion volumes by 71%. Reductions in plasma cholesterol were due to the loss of non-HDL lipoproteins, while plasma HDL-cholesterol levels were increased. At a 10-fold lower oral dose, the nanoparticles were marginally effective in reducing atherosclerotic lesions. Intriguingly, analogous results were obtained with nanolipids of the corresponding monomeric peptide. These nanolipid formulations provide an avenue for developing orally efficacious therapeutic agents to manage atherosclerosis.
File Format	HTM / HTML
ISSN	00222275
e-ISSN	15397262
DOI	10.1194/jlr.M049262
Journal	The Journal of Lipid Research
Issue Number	10
Volume Number	55
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2014-10-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Biochemistry Apolipoprotein A-i Lipoproteins, Hdl Chemistry Pharmacology Nanoparticles Receptors, Ldl Metabolism Animals Mice Mice, Knockout Peptidomimetics Genetics Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Endocrinology

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