Liposomes and Micelles to Target the Blood Pool for Imaging Purposes

Abstract

The blood pool is among body compartments of a special interest for imaging using magnetic resonance (MR) and computed tomography (CT), since with the help of selective blood-pool contrast agents blood perfusion and various cardiac parameters as well as a status of the blood flow and vascular system in any organ can be evaluated. Blood pool-specific imaging agents can also provide minimally invasive angiography, image guidance of minimally invasive procedures, oncologic imaging of angiogenesis, ascertaining organ blood volume, and identifying hemorrhage. Particulate contrast agents (such as liposomes and micelles) whose distribution is limited to the blood pool, should have a size larger than fenestrated capillaries (> 10 nm), contain the reporter (paramagnetic or radiopaque) moiety structurally incorporated within the particulate, and be able to stay in the blood long enough to obtain clinically useful images. We describe here a new generation of long-circulating Gd-loaded liposomes and iodine-loaded micelles to provide an efficient blood pool MR and CT imaging, respectively. In this study, we developed the optimized protocol to prepare a liposomal MR contrast agent with high relaxivity and narrow size distribution. Liposomes were loaded with Gadolinium (Gd) via so called polychelating amphiphilic polymer (PAP) that represents a low-molecular-weight DTPA-polylysine linked via its N-terminus to a lipid anchor, NGPE-PE. Gd-containing liposomes were additionally modified with PEG to provide the longevity in vivo. We demonstrated also that upon the intravenous administration in rabbits and dogs, a new preparation causes prolonged decrease in the blood Tl value, permits to obtain sharp and clear MR images of the vasculature, and may be considered as a potential contrast agent for MRI of the blood pool. In addition, to prepare micellar contrast agents for CT blood-pool imaging, we synthesized an iodine-containing amphiphilic block-copolymer consisting of methoxypoly(ethyleneglycol) and polylϵ,N-(triiodobenzoyl)]-L-lysine. In aqueous solutions, it forms stable micelles with an average diameter of 80 nm and an iodine content of 35–40% wt. Iodine-containing micelles were intravenously injected into rats and rabbits at a dose of 170 mg I/kg and produced significant and sustained enhancement of the blood pool (aorta and heart), liver and spleen for a period of at least 3 hours providing clear and informative CT images.

Keywords::

• Magnetic resonance imaging
• Computed tomography
• Blood pool
• Liposomes
• Micelles