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Macrophage-Specific Lipid-Based Nanoparticles Improve Cardiac Magnetic Resonance Detection and Characterization of Human Atherosclerosis

Michael J. Lipinski, MD^_*,,,,||, Juan C. Frias, PhD^_*,,¶, Vardan Amirbekian, MD^_*,,#, Karen C. Briley-Saebo, PhD^_*,, Venkatesh Mani, PhD^_*,, Daniel Samber, PE^_*,, Antonio Abbate, MD, Juan Gilberto S. Aguinaldo, MD^_*,, Davis Massey, DDS, MD, PhD^_**, Valentin Fuster, MD, PhD, George W. Vetrovec, MD, Zahi A. Fayad, PhD^_*,,,_*

^_* Translational and Molecular Imaging Institute, Mount Sinai Medical Center, New York, New York
Imaging Science Laboratories, Department of Radiology, Mount Sinai Medical Center, New York, New York
The Zena and Michael A. Wiener Cardiovascular Institute, The Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Department of Internal Medicine, Division of Cardiology, Mount Sinai Medical Center, New York, New York
VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia
^|| Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia
^¶ Instituto de Ciencia Molecular, University of Valencia, Valencia, Spain
^# Department of Radiology, Brigham and Womens Hospital, Boston, Massachusetts
^_** Department of Pathology, Virginia Commonwealth University Health System, Richmond, Virginia

^_* Reprint requests and correspondence: Dr. Zahi A. Fayad, Mount Sinai School of Medicine, One Gustave L. Levy Place, Imaging Science Laboratories, Box 1234, New York, New York 10029 (Email: zahi.fayad{at}mssm.edu).

Objectives: We sought to determine whether gadolinium (Gd)-containing lipid-based nanoparticles (NPs) targeting the macrophage scavenger receptor-B (CD36) improve cardiac magnetic resonance (CMR) detection and characterization of human atherosclerosis.

Background: Gd-containing lipid-based NPs targeting macrophages have improved MR detection of murine atherosclerosis.

Methods: Gadolinium-containing untargeted NPs, anti-CD36 NPs, and nonspecific Fc-NPs were created. Macrophages were incubated with fluorescent targeted and nontargeted NPs to determine uptake via confocal microscopy and inductively coupled plasma mass spectroscopy (ICP-MS) quantified Gd uptake. Human aortic specimens were harvested at autopsy. With a 1.5-T scanner, T1, T2, and PDW 3-dimensional scans were performed along with post-contrast scans after 24 h incubation. The T1 and cluster analyses were performed and compared with immunohistopathology.

Results: The NPs had a mean diameter of 125 nm and 14,900 Gd-ions, and relaxivity was 37 mmol/l^–1s^–1 at 1.5-T and 37°C. Confocal microscopy and ICP-MS demonstrated significant in vitro macrophage uptake of targeted NPs, whereas non-targeted NPs had minimal uptake. On T1 imaging, targeted NPs increased contrast-to-noise ratio (CNR) by 52.5%, which was significantly greater than Fc-NPs (CNR increased 17.2%) and nontargeted NPs (CNR increased 18.7%) (p = 0.001). Confocal fluorescent microscopy showed that NPs target resident macrophages, whereas 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 non-targeted NPs.

Conclusions: Macrophage-specific (CD36) NPs bind human macrophages and improve CMR detection and characterization of human aortic atherosclerosis. Thus, macrophage-specific NPs could help identify high-risk human plaque before the development of an atherothrombotic event.

Key Words: atherosclerosis • CD36 • macrophage • magnetic resonance imaging • nanoparticles

Abbreviations and Acronyms   Apo = apolipoprotein   CD204 = a class A macrophage scavenger receptor   CD36 = a class B macrophage scavenger receptor   CMR = cardiac magnetic resonance   CNR = contrast-to-noise ratio   DAPI = 4',6'-diamidino-2-phenylindole hydrochloride   DPPE-NBD = 1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-7-nitro-2-1,3-benzoxadiazol-4-yl   Gd = gadolinium   ICP-MS = inductively coupled plasma mass spectroscopy   MSR = macrophage scavenger receptor   NP = nanoparticle   PBS = phosphate-buffered solution   PDW = proton-density-weighted   RPE = phycoerythrin   SNR = signal-to-noise ratio   SPIO = superparamagnetic iron oxide particle