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Biomedical subjects

M A Longino

Publications and source records attributed to M A Longino.

At least 19 recordsLinked to original sources
PubMed2000

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.

Animals↗
PubMed2000

Combined hepatocyte-selective and blood-pool contrast agents for the CT detection of experimental liver tumors in rabbits.

PURPOSE: To determine the imaging characteristics of a new computed tomographic (CT) contrast material with both hepatocyte-selective and blood-pool components (iodinated triglyceride (ITG)-dual) versus standard iohexol. MATERIALS AND METHODS: VX2 carcinoma was inoculated in seven rabbits. Animals underwent nonenhanced, iohexol-enhanced (600 mg of iodine per kilogram of body weight), and ITG-dual-enhanced (blood-pool moiety, 100 mg of iodine per kilogram; hepatocyte-selective moiety, 100 or 200 mg of iodine per kilogram, injected 90 minutes apart) helical CT. Livers were removed, preserved in formalin, suspended in agar, and sectioned transversely at 3-mm intervals. Attenuation values for normal liver and tumors were obtained, and blinded readers evaluated images for lesions by using a modified free-response receiver operating characteristic (ROC) method. RESULTS: A total of 47 separate tumor sites were detected at pathologic examination. ITG-dual-enhanced scans obtained with 300 mg of iodine per kilogram demonstrated similar liver opacification to iohexol-enhanced scans obtained with 600 mg of iodine per kilogram, but with less lesion enhancement, which resulted in better liver-to-lesion contrast. Blinded readers had a higher sensitivity, accuracy, and area under the ROC curve for ITG-dual-enhanced scans as compared with iohexol-enhanced scans (P: <.01). CONCLUSION: ITG-dual-enhanced CT quantitatively and qualitatively improved liver lesion detection versus iohexol-enhanced CT. Future clinical trials with various human tumor types after potential approval for human use are needed to determine the ultimate role of this or other dual-mechanism contrast materials.

Animals↗
PubMed1998

Lipid-based blood-pool CT imaging of the liver.

RATIONALE AND OBJECTIVES: We 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. MATERIALS AND METHODS: Preliminary 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. RESULTS: Pharmacokinetic 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. CONCLUSION: In 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.

Animals↗
PubMed1996

Computed tomography scanning of Morris hepatomas with liver-specific polyiodinated triglycerides.

RATIONALE AND OBJECTIVES: We 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. METHODS: Eighteen 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. RESULTS: Hepatomas 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. CONCLUSION: Because 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.

Animals↗
PubMed1996

Physicochemical characterization of a synthetic lipid emulsion for hepatocyte-selective delivery of lipophilic compounds: application to polyiodinated triglycerides as contrast agents for computed tomography.

A synthetic lipid emulsion (LE) has been developed with physicochemical properties that closely resemble those of a specific class of naturally-occurring lipoproteins known as chylomicron remnants. The formulation has the potential to serve as a hepatocyte-selective delivery system for any lipophilic or amphipathic compounds that can be associated with the internal lipid phase of the emulsion. In the present studies, a lipophilic polyiodinated triglyceride (ITG) was successfully incorporated into the delivery vehicle to form a stable chylomicron-remnant-like emulsion capable of localizing material to the liver following intravenous injection. The preferred ITG-LE formulation was shown to have a mean particle diameter of less than 200 nm and a particle size stability profile in excess of 12 months. The viscosity, pH, and osmolality of the formulation also appeared favorable for safe and convenient intravenous injection. The particle size profile, chemical properties, and high degree of incorporation of ITG into the emulsion suggest that the ITG-LE formulation holds substantial promise as a hepatocyte-selective imaging agent for computed tomography of the liver. Biodistribution, elimination, and computed tomography (CT) imaging results in animals corroborated the hepatocyte-selective nature of the ITG-LE formulation.

Animals↗
PubMed1996

Formulation of polyiodinated triglyceride analogues in a chylomicron remnant-like liver-selective delivery vehicle.

PURPOSE: 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 degrees 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.

Chylomicrons↗
PubMed1995

Polyiodinated triglyceride analogs as potential computed tomography imaging agents for the liver.

A series of glyceryl 2-oleoyl 1,3-bis[omega-(3-amino-2,4,6-triiodophenyl)] alkanoates was synthesized, radioiodinated with iodine-125, emulsified, and evaluated for their ability to selectively localize in the liver for potential use as hepatographic agents in computed tomography. All seven analogs displayed rapid liver uptake wherein between 65 and 78% of the injected dose accumulated in the liver by 30 min. Liver values ranged from 46 to 93% 3 h after injection which corresponded to liver to blood ratios ranging from 21 to 450. Moreover, subsequent elimination of radioactivity from the liver was nearly linear with respect to alkyl chain length. Analogs with longer alkyl chain length were eliminated from the liver more rapidly than their shorter chain counterparts. Because of their biochemical similarities to naturally occurring triglycerides, these novel analogs may prove useful not only for high-resolution anatomic imaging of focal liver lesions, but also for evaluating a variety of diffuse diseases known to affect hepatic function and biochemistry.

Animals↗
PubMed1992

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.

Animals↗
PubMed1989

Lipoprotein incorporation enhances radioiodinated cholesteryl ester uptake into steroid hormone-secreting tissues.

This study was undertaken to determine whether incorporation of radioiodinated cholesterol derivatives into plasma lipoproteins prior to administration to animals could lead to improvements in adrenal localization of radioactivity. Rat high density lipoproteins (HDL) were labeled with [125I]cholesteryl iopanoate, a nonhydrolyzable ester of cholesterol. No enhancement in adrenal uptake of radioactivity was noted at 30 min following administration of the HDL preparation to control rats when compared with [125I]NP-59. However, when animals were made hypolipidemic by treatment with either 4-APP or ethinyl estradiol, the adrenal radioactivity after i.v. administration of the HDL preparation was found to be over 15 times greater than that achieved with [125I]NP-59. Scans of hypolipidemic rats taken at 30 min correlated well with the tissue distribution results.

Adrenal Cortex↗
PubMed1988

Iodine-125 cholesteryl iopanoate for measuring extent of atherosclerosis in rabbits.

Rabbits rendered atherosclerotic by mechanical aortic de-endothelialization and 6 wk of cholesterol feeding were administered estradiol-17 beta-cypionate, an anti-atherogenic agent in rabbits. These animals were compared to a similar, untreated group and control animals fed a regular non-atherogenic diet. Iodine-125 cholesteryl iopanoate ([125I]Cl), a nonhydrolyzable cholesteryl ester derivative, was administered intravenously at regular intervals throughout the study. Six days after the last dose of [125I]Cl, the animals were scanned with a gamma camera. After animals were killed, tissue distribution of the 125I radioactivity showed a significant decrease of [125I]CI accumulation in the aorta of estrogen-treated as compared to untreated, cholesterol-fed animals. However, the accumulation of [125I]CI in the aortas was insufficient to accurately define the presence of atheroma by gamma camera scintigraphy.

Animals↗
PubMed1986

Potential tumor- or organ-imaging agents. 26. Polyiodinated 2-substituted triacylglycerols as hepatographic agents.

A series of omega-(3-amino-2,4,6-triiodophenyl)alkanoic acids and the corresponding 1,3-dipalmitoylglycerol 2-[omega-(3-amino-2,4,6-triiodophenyl)alkanoates] were synthesized, radioiodinated with iodine-125, and evaluated for their ability to selectively localize in the liver for potential use as hepatographic imaging agents. Acid analogues 1d and 1e afforded relatively high levels of radioactivity in the liver (45 and 49% injected dose) 5 min after intravenous administration to rats. These acids displayed a marked propensity to become bound to plasma albumin. In contrast, triacylglycerol analogues 10a and 10c did not become immediately associated with plasma albumin but instead rapidly became associated with plasma lipoproteins and showed a different tissue distribution profile than free acids 1a and 1c. Although long-chain triacylglycerol analogues 10d and 10e exhibited some capacity to accumulate in the liver at 5 and 30 min, respectively, analysis of the plasma revealed significant in vivo ester hydrolysis. It would thus appear that liver radioactivity following administration of 10d and 10e was due to uptake of the free acid and not the intact triacylglycerol. Triacylglycerol analogues 10a and 10c, on the other hand, were taken up intact and showed liver accumulations of 25 and 35% of the administered dose at 30 min.

Animals↗
PubMed1986

Potential tumor- or organ-imaging agents. 27. Polyiodinated 1,3-disubstituted and 1,2,3-trisubstituted triacylglycerols.

A series of glyceryl 1,3-bis- and 1,2,3-tris[omega-(3-amino-2,4,6-triiodophenyl)alkanoates] were synthesized, radioiodinated with iodine-125, and evaluated for their ability to selectively localize in the liver for potential use as hepatographic imaging agents. Of the nine target compounds synthesized and evaluated in rats, glyceryl 1,2,3-tris[3-(3-amino-2,4,6-triiodophenyl)propionate] (5b) displayed rapid and sustained liver specificity. This agent was found to accumulate in the liver in concentrations of 60, 75, and 86% of the administered dose at 5 min, 30 min, and 24 h, respectively. Moreover, the 24-h liver-to-blood ratio of 235 justifies further studies in higher animal species.

Animals↗
PubMed1984

Esters of iopanoic acid as liver-specific CT contrast agents: biodistribution and CT evaluation.

The synthesis and preliminary biodistribution data for a series of sterol-like esters of iopanoic acid having potential value as liver-specific CT contrast agents are described. Structural modification of the sterol portion of the iopanoate ester afforded a group of compounds that displayed tissue specificity similar to cholesteryl iopanoate, the prototype ester of this series, but were rapidly cleared from the target tissues after hydrolysis. From the biodistribution data, the most promising of these agents, pregnenolone iopanoate (PI), was evaluated by CT in rabbits receiving a radiologic dose equivalent to 30 mg I/kg. The hepatic parenchyma was enhanced within 2 h of infusion to a maximal level of 31 HU above precontrast values. Hepatic CT attenuation returned to normal within 24 h. However, CT performed after PI infusion into Vx2 tumor-bearing rabbits failed to provide superior images compared with those acquired following bolus administration of urographic contrast.

Adenocarcinoma↗
PubMed1983

Lipid soluble contrast agents for computed tomography of the liver: results with cholesteryl iopanoate.

A new class of compounds, polyiodinated sterol esters, has recently been synthesized and found to have characteristics suggesting potential value as site-specific hepatic computed tomographic (CT) contrast agents. A prototype compound, cholesteryl iopanoate, was administered intravenously to rabbits in doses of 65 mg I/kg. The compound was found to significantly enhance hepatic parenchyma to a maximal level of 65 Hounsfield units (HU) above base-line values without observable splenic enhancement. A subsequent study comparing the administered dose with the change in CT attenuation values of liver demonstrated that near-maximum enhancement reaching 22 HU was achieved at a dose of 30 mg I/kg within 24 h after injection. The enhancement characteristics suggest the mechanism of hepatic accumulation may not be mediated solely by the reticuloendothelial system. Administration of cholesteryl iopanoate (30 mg I/kg) to rabbits with hepatic tumors (V x 2 adenocarcinoma) resulted in the CT imaging of tumors as small as 2 mm in diameter. Further investigation of this new class of lipid-soluble contrast agents seems warranted.

Animals↗
PubMed1982

Potential tumor- or organ-imaging agents. 23. Sterol esters of iopanoic acid.

A series of sterol esters of iopanoic acid was synthesized and evaluated for their potential to selectively localize in liver and steroid-secreting tissues for possible application in either computed tomography or nuclear medicine imaging. Unlike free iopanoic acid (1), which was rapidly cleared following intravenous administration to rats, cholesteryl iopanoate (2) was found to accumulate in liver, adrenal cortex, and ovary. At 24 h, the ovary was found to contain the highest concentration of 2. The ability of 2 to accumulate in the above tissues was attributed to its resistance to hydrolysis. Pregnenolone iopanoate (3) and dehydroepiandrosterone iopanoate (4), on the other hand, were shown to reach unusually high concentrations in the adrenal cortex within 0.5 h of administration but declined to much lower levels by 24 h. Lipid extraction of tissues showed 3 and 4 to be susceptible to in vivo hydrolysis, which undoubtedly was a major factor in their clearance from adrenal tissue.

Animals↗
PubMedDate not supplied

Biotinylated granulocyte/macrophage colony-stimulating factor analogues: effect of linkage chemistry on activity and binding.

Biotinylated granulocyte/macrophage colony-stimulating factor (GM-CSF) analogues with different linkage chemistries and levels of conjugated biotin were synthesized by reacting recombinant human GM-CSF with sulfosuccinimidyl 6-biotinamidohexanoate or biotin hydrazide/1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide. These chemically reactive forms of biotin produced derivatives biotinylated at amine or carboxyl groups, respectively. Amine-derivatized analogues of 1.2 and 3.8 mol of biotin/mol of protein (N1-bGM-CSF and N4-bGM-CSF) and a carboxyl-modified analogue of 4.6 mol of biotin/mol of protein (C5-bGM-CSF) were synthesized. These analogues were compared to determine the effect of biotinylation on biological activity and GM-CSF receptor binding characteristics. The biotinylated proteins migrated with the same molecular weight as the native, unmodified protein as determined by SDS-PAGE and could be detected by Western blotting with alkaline phosphatase conjugated streptavidin, thus demonstrating the biotin linkage. All three analogues retained full agonist activity relative to the native protein (EC50 = 10-15 pM) when assayed for the stimulation of human bone marrow progenitor cell growth. Cell surface GM-CSF receptor binding was characterized by the binding of the analogues to human neutrophils, with detection by fluorescein-conjugated avidin and fluorescence-activated cell sorting. The N-bGM-CSFs demonstrated GM-CSF receptor specific binding that was displaceable by excess underivatized protein, with the detected fluorescence signal decreasing with increasing biotin to protein molar ratio. In contrast, C5-bGM-CSF binding above background fluorescence could not be detected using this system, suggesting that this derivative could bind to and activate the receptor, but not simultaneously bind fluorescein-conjugated avidin. The amine-derivatized biotinylated GM-CSF analogues retained biological activity, could specifically label cell surface receptors, and may be useful nonradioactive probes with which to study GM-CSF receptor cytochemistry and receptor modulation by flow cytometry.

Biological Assay↗