MR contrast based on modified HDL enhances atherosclerotic plaques

June 1, 2005

Dr. Zahi Fayad and Dr. Juan C. Frias at Mount Sinai School of Medicine in New York City and Dr. Edward Fisher at New York University School of Medicine have developed a high-density lipoprotein (HDL)-like nanoparticle for imaging atherosclerotic plaques in vivo. The researchers removed lipids from normal human HDL cholesterol. Apolipoproteins were extracted and reconstituted with the phospholipid-based contrast agent gadolinium-DTPA-DMPE and NBD-DPPE, a fluorescent phospholipid with a green emission. The Gd-DTPA-DMPE becomes incorporated in the reconstituted particle. (An approximately 9-nm diameter contains 15 to 20 molecules of Gd-DTPA-DMPE.)

CONTEXT: Dr. Zahi Fayad and Dr. Juan C. Frias at Mount Sinai School of Medicine in New York City and Dr. Edward Fisher at New York University School of Medicine have developed a high-density lipoprotein (HDL)-like nanoparticle for imaging atherosclerotic plaques in vivo. The researchers removed lipids from normal human HDL cholesterol. Apolipoproteins were extracted and reconstituted with the phospholipid-based contrast agent gadolinium-DTPA-DMPE and NBD-DPPE, a fluorescent phospholipid with a green emission. The Gd-DTPA-DMPE becomes incorporated in the reconstituted particle. (An approximately 9-nm diameter contains 15 to 20 molecules of Gd-DTPA-DMPE.)

RESULTS: Sequential MRI revealed that reconstituted HDL (rHDL) localized mainly around the atherosclerotic plaque within 24 hours after injection in hyperlipidemic mice. Signal intensity correlated with cellular content. Contrast persisted for 48 hours. In vitro, fluorescent microscopy performed 24 hours after contrast injection showed that fluorescence concentrated in the intimal layer of the aorta where lipids accumulate. In control experiments, Gd-DTPA-DMPE without HDL was injected into mice. Imaging revealed that the contrast agent without the HDL accumulated and was retained in plaque for more than 48 hours, whereas the signal with the rHDL-Gd particles was significantly reduced by 48 hours.

"The rHDL-Gd particles have proven to have a greater transience and greater penetrations than Gd-DTPA-DMPE alone," Fayad said.

IMAGE: In vivo MR images were acquired immediately following (left) and 24 hours after injection of a 4.36-mmol/kg injection of rHDL-Gd contrast. Dosage was determined by inductively coupled plasma mass spectrometry measurements. White arrows indicate abdominal aorta, and the inset denotes a magnification of the aortic region.

IMPLICATIONS: Early experience suggests that the HDL-like particles may be effective for imaging atherosclerotic plaques because of their high gadolinium-carrying capacity. Reconstituted HDL may also have therapeutic implications.

"These results look promising, and the next step is to go to clinical trials," Fayad said. "Also, the research does not stop with plaque detection. The platform we developed can be modified with small peptides or antibodies so we can target specific tissues, cells, and proteins."