Marc A. Longino

Lipid-based blood-pool CT imaging of the liver

RATIONALE AND OBJECTIVESnWe have recently developed an iodinated lipid-based contrast agent capable of residing in the blood pool for extended periods of time relative to conventional water-soluble contrast agents. The purpose of this study was to examine the effects of combining this new blood-pool agent (ITG-PEG) with a hepatocyte-selective agent (ITG-LE; Molecular Biosystems) for accurate CT detection of small (< 10 mm) VX2 tumors in rabbit liver.nnnMATERIALS AND METHODSnPreliminary pharmacokinetic analyses were conducted in SD rats (12) by injection of either I-125-labeled ITG-PEG or I-125-labeled ITG-LE followed by subsequent blood collection and quantification of radioactivity. Preliminary CT studies were conducted in both normal (3) and tumor-bearing NZW rabbits (2). Tumor-bearing rabbits were laparotomized and VX2 cells injected directly into the hepatic parenchyma to produce a total of eight focal lesions (2-10 mm diameter). Animals underwent CT scanning 10 days later with multiple techniques including noncontrast and helical i.v. enhanced (600 mg I/kg iohexol), and then 24 hours later using both ITG-PEG and ITG-LE (200 mg I/kg). Tissue density measurements (HU) of liver, tumor, and blood (descending aorta) were acquired in each case for comparison. Tumor morphology was verified by gross pathologic inspection.nnnRESULTSnPharmacokinetic analysis in rats as well as CT studies in normal rabbits revealed that ITG-PEG remains in the blood-pool phase for more than 2 hours following i.v. administration. In fact, blood density in normal rabbit obtained with ITG-PEG was 95.1 HU +/- 5.8 at 120 minutes compared to 90.7 HU +/- 6.1 immediately after injection. Although liver enhancement was greater with iohexol (67 HU within 1 minute of injection), than for ITG-PEG/ITG-LE (32 HU, 60 minutes postinjection), liver to lesion ratios favored ITG-PEG/ITG-LE due to significant enhancement of tumor itself with iohexol (+40 HU). Tumor enhancement was minimal with ITG-PEG/ITG-LE. Lesions were subjectively much better defined with ITG-PEG/ITG-LE with sharper edge definition.nnnCONCLUSIONnIn these animal models, a new iodinated lipid-based contrast agent composed of both blood pool and hepatocyte-selective components afforded favorable CT imaging results compared to a conventional urographic agent, albeit at one-third the total iodine dose.

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).nMethods. 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.nResults. 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.nConclusions. 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.

A surface-modified chylomicron remnant-like emulsion for percutaneous computed tomography lymphography: synthesis and preliminary imaging findings.

Wisner ER, Weichert JP, Longino MA, et al. A surface-modified chylomicron remnant-like emulsion for percutaneous computed tomography lymphography: synthesis and preliminary imaging findings. Invest Radiol 2002;37:232-239. Rationale and objectives. To assess a surface-modified emulsion as a percutaneous CT lymphographic agent in normal dogs. methods. An iodinated chylomicron remnant-like microemulsion was formulated with a mean particle size of 91.3 nm and an iodine concentration of 91 mg I/mL. Contrast material (2 mL) was injected into the subcutaneous tissues of the metatarsus and metacarpus of six normal dogs to enhance popliteal and cervical lymph nodes, respectively. CT images were acquired at 0, 15, 30, 45, 60, 240, 480, and 1440 minutes. results. Significant lymph node enhancement occurred in as little as 15 minutes after injection and persisted at least 8 hours. Node opacification was most pronounced at 1 to 4 hours postinjection and exceeded 200 HU in some nodes (precontrast attenuation = 45 HU). Marked enhancement of popliteal efferent lymphatics and of iliac and sacral node groups also occurred indicating distribution to second order nodes. Attenuation of enhanced nodes reverted to precontrast levels by 24 hours. conclusion. The new surface-modified, chylomicron remnant-like emulsion provided marked, selective enhancement of targeted lymph nodes after subcutaneous administration. Moreover, the formulation produced significant opacification of more distant node groups from a single injection.

Computed tomography scanning of morris hepatomas with liver-specific polyiodinated triglycerides

RATIONALE AND OBJECTIVESnWe compared the computed tomography (CT) scanning characteristics of a polyiodinated triglyceride analog with those of a urographic agent to distinguish Morris-7777 hepatoma (MH) cells from normal hepatocytes in rats.nnnMETHODSnEighteen Buffalo rats were laparotomized and MH cells injected directly into the hepatic parenchyma or introduced via the portal vein to produce, respectively, focal or diffuse lesions in the liver. Baseline CT scans were obtained 21 days after implantation and prior to intravenous administration of either the polyiodinated triglyceride (45-100 mg I/kg) or the nonionic contrast agent, iohexol (560 mg I/kg). Images were obtained at 0-3 hr and 24 hr. Gross pathologic inspection was performed to validate the imaging results.nnnRESULTSnHepatomas were nearly isodense with normal liver parenchyma in many of the animals, rendering lesion detection difficult with no contrast agent. The bolus administration of iohexol improved lesion detection in many cases. Lesion conspicuity, however, was significantly improved with the polyiodinated triglyceride at less than one eighth the dose of iohexol.nnnCONCLUSIONnBecause of their biochemical nature, polyiodinated triglyceride analogs are specifically cleared by the liver. Consequently, they offer several advantages over nonspecific urographic agents in their ability to enhance lesion conspicuity in this hepatoma model.

Biodistribution of a new lipid-soluble CT contrast agent. Evaluation of cholesteryl iopanoate in the rabbit.

Cholesteryl iopanoate, the prototype for a new class of lipid-soluble, site-specific contrast agents, has undergone preliminary evaluation for organic-specific uptake. This report describes the tissue distribution profile of this radioiodinated sterol ester in the rabbit as a function of time following intravenous injection of tracer doses. Selective accumulation of this agent in the liver and adrenal was observed relative to blood and other tissues. Maximum contrast concentration was achieved between 24 and 48 hours postinjection. Analysis of lipid extra of liver, adrenal, and plasma indicated that the compound was relatively resistant to hydrolysis and dehalogenation. The hepatic selectivity and retention of cholesteryl iopanoate support further study of this or related agents for site-specific, contrast-enhanced computed tomography.

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.

Potential Organ or Tumor Imaging Agents. 32. A Triglyceride Ester of p-Iodophenyl Pentadecanoic Acid as a Potential Hepatic Imaging Agent

A triglyceride analog, glycerol-2-palmitoyl-1,3-di-15-(p-iodophenyl)pentadecanoate (DPPG) was synthesized and radiolabeled for evaluation as a potential functional liver scintigraphic agent. Uptake of DPPG was compared in normal, diabetic, tumor-bearing and heparin pretreated rats, revealing differences in uptake and clearance of radioactivity, correlating with hepatic lipase activity of these groups. Similar results were observed by gamma-camera scintigraphy. Comparing the uptake of DPPG with that of its fatty acid component, 15-(p-iodophenyl)pentadecanoic acid (IPPA), revealed that the peak uptake of IPPA in the liver was about half that of DPPG. Based upon these findings, DPPG warrants further study as a hepatic radiodiagnostic agent.