EXPERIMENTAL STUDIES
In vivo targeting of acoustically reflective liposomes for intravascular and transvascular ultrasonic enhancement
Sasha M. Demos, PhD*,
Hayat Alkan-Onyuksel, PhD*  ,
Bonnie J. Kane, BS ,
Kishin Ramani, MD,
Ashwin Nagaraj, PhD,
Rodney Greene, BS,
Melvin Klegerman, PhD and
David D. McPherson, MD
* Department of Bioengineering, University of Illinois/Chicago, Chicago, Illinois, USA
Department of Pharmaceutics and Pharmacodynamics, University of Illinois/Chicago, Chicago, Illinois, USA
Feinberg Cardiovascular Research Institute, Northwestern University Medical School, Chicago, Illinois, USA
Manuscript received April 22, 1998;
revised manuscript received September 25, 1998,
accepted November 5, 1998.
Reprint requests and correspondence: Dr. Sasha M. Demos, c/o Dr. David D. McPherson, Northwestern Memorial Hospital, Cardiology/Medicine, 250 East Superior Street—Wesley 520, Chicago, Illinois 60611
d.mcpherson{at}nwu.edu
OBJECTIVES
The purpose of this study was to target acoustically reflective liposomes to atherosclerotic plaques in vivo for ultrasound image enhancement.
BACKGROUND
We have previously demonstrated the development of acoustically reflective liposomes that can be conjugated for site-specific acoustic enhancement. This study evaluates the ability of liposomes coupled to antibodies specific for different components of atherosclerotic plaques and thrombi to target and enhance ultrasonic images in vivo.
METHODS
Liposomes were prepared with phospholipids and cholesterol using a dehydration/rehydration method. Antibodies were thiolated for liposome conjugation with N-succinimidyl 3-(2-pyridyldithio) propionate resulting in a thioether linkage between the protein and the phospholipid. Liposomes were conjugated to antifibrinogen or anti–intercellular adhesion molecule-1 (anti–ICAM-1). In a Yucatan miniswine model, atherosclerosis was developed by crush injury of one carotid and one femoral artery and ingestion of a hypercholesterolemic diet. After full plaque development the arteries were imaged (20-MHz intravascular ultrasound catheter and 7.5-MHz transvascular linear probe) after injection of saline, unconjugated liposomes and antibody conjugated liposomes.
RESULTS
Conjugated liposomes retained their acoustically reflective properties and provided ultrasonic image enhancement of their targeted structures. Liposomes conjugated to antifibrinogen attached to thrombi and fibrous portions of the atheroma, whereas liposomes conjugated to anti–ICAM-1 attached to early atheroma.
CONCLUSIONS
Our data demonstrate that this novel acoustic agent can provide varying targeting with different antibodies with retention of intravascular and transvascular acoustic properties.
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Abbreviations and Acronyms
| | ATH | = atherosclerosis | | BAP | = brightness area product | | DPPG | = 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol | | DTT | = dithiothreitol | | ICAM-1 | = intercellular adhesion molecule-1 | | MPB-PE | = maleimido-4 (p-phenylbutyrate)-phosphatidylethanolamine | | PC | = phosphatidylcholine | | SPDP | = 3-(2-pyridyldithiolpropionic acid N-hydroxysuccinimide ester |
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