Author + information
- Received July 17, 2008
- Accepted August 19, 2008
- Published online May 1, 2009.
- 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§ and
- Zahi A. Fayad, PhD⁎,†,‡,⁎ ()
- ↵⁎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
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.
This study was supported in part by NIH/NHLBI ROI HL71021, NIH/NHLBI HL078667 (to Dr. Fayad), and the Stanley J. Sarnoff Endowment for Cardiovascular Research, Inc. (to Dr. Amirbekian). The MSSM-Microscopy Shared Resource Facility is supported by funding from NIH-NCI shared resources Grant R24 CA095823, and NSF Major Research Instrumentation Grant DBI-9724504.
- Received July 17, 2008.
- Accepted August 19, 2008.
- American College of Cardiology Foundation