Douglas A. Bakan

Polyiodinated triglyceride lipid emulsions for use as hepatoselective contrast agents in CT: effects of physicochemical properties on biodistribution and imaging profiles.

RATIONALE AND OBJECTIVES A novel lipid emulsion (LE) was developed for hepatoselective delivery of a polyiodinated triglyceride (ITG) with potential for use in CT. This work assessed the effects of mean particle size, total administered dose, and formulation composition on the in vivo biodistribution and imaging profiles of the ITG-LE in rats. METHODS The concentration of radioactivity derived from intravenously administered 125I-ITG-LE was determined as a function of time after injection. CT imaging studies of the abdomen evaluated the extent of hepatic enhancement after administration of ITG-LE. RESULTS Mean emulsion particle diameter and total administered dose exerted the greatest effect on ITG-LE biodistribution profiles. In the optimal delivery scenario, >70% of the administered dose localized to the liver 30 minutes after injection. Liver enhancement profiles in CT imaging studies were consistent with biodistribution profiles. CONCLUSIONS These results suggest that an appropriately formulated and administered dose of ITG-LE provides tissue-selective localization of contrast material for use in CT.

Formulation of Polyiodinated Triglyceride Analogues in a Chylomicron Remnant-Like Liver-Selective Delivery Vehicle

AbstractPurpose. A formulation methodology for the incorporation of polyiodinated triglyceride (ITG) analogues into a protein-free chylomicron remnant-like emulsion was developed to provide a vehicle for the selective hepatic delivery of these agents for contrast-enhanced X-ray computed tomography (CECT). Methods. Triglyceride emulsions (10% w/v) were prepared at various processing pressures, temperatures and times with a Microfluidizer® 110-S using different emulsion component proportions to establish processing and compositional parameters in order to afford stable ITG emulsions (ITG-LE) approaching 200 nm mean diameter. Results. Preliminary data indicated that with a formulation composed of 2.4% dioleoyl PC with a cholesterol:DOPC mole ratio of 0.4 emulsified at 14,700 psi, 35°C for 10 min routinely afforded ITG-LE in the desired size range. The elimination of salt and amino acid from the bulk phase enhanced the stability of the ITG-LE. Incorporation of cholesterol into the monolayer was of critical importance in generating a stable emulsion near the targeted size, with a C:DOPC mole ratio of 0.4 producing a size minimum relative to higher or lower C:DOPC values. Conclusions. The ITG analogues can be readily incorporated into stable remnant-like emulsions of relatively uniform particle size. Combination of the unique ITG contrast agent with the remnant-like delivery vehicle demonstrates a high degree of hepatic selectivity in biodistribution studies and offers significant potential for selective hepatic CECT.

Imaging efficacy of a hepatocyte-selective polyiodinated triglyceride for contrast-enhanced computed tomography.

Rationale and objectivesDHOG-LE is an injectable polyiodinated triglyceride lipid emulsion providing contrast enhancement of the liver in CT. Studies were conducted to characterize the imaging efficacy of various DHOG-LE formulations as a function of both the administered iodine dose and the formulation composition. Materials and methodsFour DHOG-LE preparations consisting of either 10, 20, 25, or 30% (w/v) total lipid were administered to anesthetized female Sprague Dawley rats as single intravenous bolus doses of 50, 100, 150, and/or 300 mg I/kg (n = 3 to 6 rats/formulation and dose). A 25% triolein lipid emulsion prepared without iodine was administered as a vehicle control at the highest dose volume (n = 6). Liver enhancement was evaluated as a function of time (0 to 24 hours) after administration of contrast by analyzing regions of interest from sequential body scans. ResultsAt all dose levels, liver enhancement was observed after injection of each DHOG-LE formulation. Regardless of formulation composition, similar enhancement of the liver was noted when administered at an equivalent iodine dose. Liver enhancement increased proportionately with increasing iodine dose. Mean peak intensities for 50, 100, 150, and 300 mg I/kg doses were 78 HU (42% above baseline), 101 HU (84% above baseline), 125 HU (127% above baseline), and 195 HU (255% above baseline), respectively. Liver time-intensity profiles exhibited rapid uptake, prolonged enhancement up to 3 hours, and complete clearance of the majority of the formulations tested by 24 hours. Time and duration of peak intensities were also directly related to iodine dose. ConclusionsIn the animal model tested, DHOG-LE imaging efficacy was directly related to iodine dose and was independent of formulation composition. Thus, administration of DHOG-LE in highly concentrated lipid preparations minimized administered dose volume and resulted in appreciable liver enhancement, even at the lowest dose of 50 mg I/kg.

Imaging Efficacy of a Hepatocyte-Selective Polyiodinated Triglyceride (DHOG-LE) for Contrast–enhanced CT

RATIONALE AND OBJECTIVES In spite of the widespread use of water-soluble contrast media for computed tomography (CT), an organ-selective contrast agent is still seen as a desirable goal of radiology research (1–3). With its high incidence of primary and metastatic lesions and parenchymal pathology, the liver is one organ system that is likely to benefit from a targeted imaging agent. Although a number of attempts have been made toward developing a safe and effective hepatic CT contrast agent ( 4 –6), a commercially available product resulting from these efforts has yet to become available to clinicians. We have previously introduced and characterized a hepatocyte-selective CT contrast agent consisting of a polyiodinated triglyceride (ITG) in a lipid emulsion (LE) delivery system designed to participate in the naturally occurring lipoprotein metabolism pathways in the liver (7–9). Although this early formulation was effective in providing considerable hepatic opacification for prolonged periods of time after injection, the volumes required for achieving high levels of liver enhancement were potentially limiting. In an effort to reduce the volumes of material required for visualization of hepatic anatomy and pathology by CT, a series of high-concentration ITG-LE formulations was developed (10). The current work extends these improvements and characterizes the imaging efficacy of these high-concentration ITG-LE formulations in normal rats.