Development of Contrast Agents Targeted to Macrophage Scavenger Receptors for MRI of Vascular Inflammation

Abstract

Atherosclerosis is a leading cause of death in the U.S. Because there is a potential to prevent coronary and arterial diseases through early diagnosis, there is a need for methods to image arteries in the subclinical stage as well as clinical stage using various non-invasive techniques, including Magnetic Resonance Imaging (MRI). We describe a development of a novel MRI contrast agent targeted to plaques that will allow imaging of lesion formation. The contrast agent is directed to macrophages, one of the earliest components of developing plaques. Macrophages are labeled through the macrophage scavenger receptor A, a macrophage specific cell surface protein, using an MRI contrast agent derived from scavenger receptor ligands. We have synthesized and characterized these contrast agents with a range of relaxivities. In vitro studies show that the targeted contrast agent accumulates in macrophages and solution studies indicate that micromolar concentrations are sufficient to produce contrast in an MR image. Cell toxicity and initial biodistribution studies indicate low toxicity, no detectable retention in normal blood vessels, and rapid clearance from blood. The promising performance of this contrast agent targeted towards vascular inflammation opens doors to tracking of other inflammatory diseases such as tumor immunotherapy and transplant acceptance using MRI.

Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI

“…Recently, investigators used BSA to deliver Gd to macrophages ex vivo and in vitro (29). However, in vivo data are currently not available, and the specificity of targeting with albumin remains to be seen, because it is a ubiquitous substance that is taken up by many tissues and diffuses into interstitial spaces nonspecifically.…”

The Integration of Positron Emission Tomography With Magnetic Resonance Imaging

“…MRI scanners are a natural and available source for such a strong magnetic field, and the concept of PET/MRI was therefore explored. A number of experimental studies and Monte Carlo simulations have studied this effect [11]- [13], and for fields above 4.7 T and radionuclides such as 15 O, 68 Ga, and 82 Rb, the effects can be significant (Fig. 2).…”

“…In work recently reported by our group, we have generated gadolinium-based MRI contrast agents and iron oxide-based probes that can be labeled with 64 Cu for PET imaging [68], [69]. These agents have potential for dualmode PET/MRI imaging of vascular inflammation.…”

“…2) Mal-BSA Dual Mode PET/MRI Probe Synthesis: We have synthesized and characterized a biomolecule-based agent using the ligand maleylated bovine serum albumin (mal-BSA) [68]. As illustrated earlier, this agent is composed of mal-BSA conjugated to chelated Gd 3þ , paramagnetic ion for MRI contrast, and the radionuclide 64 Cu for PET.…”

Multimodal imaging of mouse development: Tools for the postgenomic era

“…MRI contrast agents generally work by shortening relaxation times, providing greater contrast-to-noise and sometimes reducing the data acquisition time. The production of contrast agents for MRI has become an area of intense investigation over the past few years, yielding many molecules that can now be used to highlight specific processes or structures (see Hogemann et al, 2000;Weissleder et al, 2000;Meade et al, 2003;Pautler and Fraser, 2003;Zhang et al, 2003;Allen and Meade, 2004;Wadghiri et al, 2004;Cunningham et al, 2005;Kelly et al, 2005;Louie, 2005Louie, , 2006Woods et al, 2005;Caruthers et al, 2006;Gustafsson et al, 2006;Pautler, 2006). Because of the noninvasive properties of MRI imaging and the ease of manipulating the mouse genome, it would be highly beneficial to have genetically encoded reporters for MRI imaging.…”