Macrophage-Specific Lipid-Based Nanoparticles Improve MRI Detection and Characterization of Human Atherosclerosis

Objectives—We sought to determine if gadolinium (Gd)-containing lipid-based nanoparticles (NPs) targeting the macrophage scavenger receptor-B (CD36) improve magnetic resonance (MR) detection and characterization of human atherosclerosis. Background—The ability to detect atherosclerosis with MR imaging using gadolinium Gdcontaining lipid-based NPs targeting macrophages may enable early detection of high-risk lesions prior to an atherothrombotic event. Gd-containing lipid-based NPs targeting macrophages improved MR detection of murine atherosclerosis. Methods—Gd-containing NPs, anti-CD36 NPs and Fc-NPs were created. Macrophages were incubated with fluorescent targeted and non-targeted NPs to determine uptake via confocal microscopy and inductively coupled plasma mass spectroscopy (ICP-MS) quatified Gd uptake. Human aortic specimens were harvested at autopsy. Using a 1.5 T scanner, T1, T2, and PDW 3dimensional scans were performed along with post-contrast scans after 24 h incubation. T1 and cluster analysis were performed and compared with immunohistopathology. © 2009 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved Corresponding Author: Zahi A. Fayad, PhD, FAHA, FACC Mount Sinai School of Medicine One Gustave L. Levy Place Imaging Science Laboratories Box 1234 New York, NY 10029 Fax: 212-534-2683 Telephone: 212-241-6858 zahi.fayad@mssm.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author Manuscript JACC Cardiovasc Imaging. Author manuscript; available in PMC 2010 May 1. Published in final edited form as: JACC Cardiovasc Imaging. 2009 May ; 2(5): 637–647. doi:10.1016/j.jcmg. 2008.08. 009. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript Results—The NPs had a mean diameter of 125 nm, 14,900 Gd-ions, and relaxivity was 37 mM-1s-1 at 1.5T and 37°C. Confocal microscopy and ICP-MS demonstrated significant in vitro macrophage uptake of targeted NPs while non-targeted NPs had minimal uptake. On T1 imaging, targeted NPs increased CNR by 52.5% which was significantly great than Fc-NPs (CNR increased 17.2%) and non-targeted NPs (CNR increased 18.7%) (p=0.001). Confocal fluorescent microscopy showed that NPs target resident macrophages while the untargeted NPs and Fc-NPs are found diffusely throughout the plaque. Targeted NPs had a greater signal intensity increase in the fibrous cap compared with (p<0.001) while non-targeted NPs and Fc-NPs had a greater increase in the lipid core (p<0.01). Conclusion—Macrophage-specific (CD36) NPs bind human macrophages and improved MR detection and characterization of human aortic atherosclerosis. Thus, macrophage-specific NPs could help identify high-risk human plaque prior to the development of an atherothrombotic event.