BACKGROUND: Oxidatively modified low-density lipoprotein (LDL) is present in atherosclerotic but not normal arteries and plays a crucial role in the pathogenesis and adverse consequences of atherosclerotic lesions. We previously generated a series of monoclonal antibodies (MoAb) against oxidation-specific neo-epitopes formed during the oxidative modification of LDL. MDA2, a prototype MoAb, recognizes malondialdehyde-lysine epitopes (eg, in malondi-aldehyde-modified LDL) within atherosclerotic lesions. We describe the in vivo characteristics of MDA2 and initial noninvasive imaging studies of atherosclerosis in rabbits. METHODS: To assess the in vivo specificity of MDA2 for atherosclerotic lesions, iodine 125-MDA2 was intravenously injected into 7 LDL-receptor deficient Watanabe heritable hyperlipidemic (WHHL) and 2 normal New Zealand white (NZW) rabbits, and the aortic plaque uptake was evaluated 24 hours later. 125I-Halb, an isotype-matched irrelevant MoAb that binds to human albumin, was injected into 5 WHHL and 2 NZW rabbits as a control. Aortic autoradiography was performed, and the mean uptake of MoAbs was measured as the percent injected dose per gram aortic tissue. Gamma camera imaging was then carried out in 7 WHHL rabbits and 2 NZW rabbits with 99mTc-MDA2. Imaging was carried out at 10 minutes and at 12 or 24 hours. Malondialdehyde-LDL was then injected to clear the blood pool signal, and final images were obtained 2 hours later. RESULTS: Mean uptake of 125I-MDA2 in the entire aorta was 17.4-fold higher in WHHL than in NZW aortas (P < .001), and 2.8-fold higher than 125I-Halb in WHHL aortas. 125I-MDA2 also had higher specificity for lesioned areas than 125I-Halb (plaque/normal ratio 6.3 vs 2.9, P < .001). Autoradiograph of aortas of 125I-MDA2-injected WHHL rabbits revealed uptake in lipid-stained lesions with absence of signal in adjacent normal arterial tissue. Immunostaining of WHHL lesions, which accumulated MDA2 as noted on autoradiography, revealed that uptake was highest in areas with abundant foam cells and in lipid-rich necrotic core areas. Autoradiograph of aortas from NZW rabbits injected with 125I-MDA2 did not yield any visible signal. Planar gamma camera in vivo scintigraphy revealed a visible signal in 4/7 WHHL rabbits, which was confirmed by aortic Sudan staining. CONCLUSION: Radiolabeled MDA2 shows excellent in vivo uptake and specificity for atherosclerotic lesions containing abundant oxidation-specific epitopes. The in vivo imaging studies suggest that noninvasive imaging of oxidation-rich atherosclerotic lesions with radiolabeled MDA2 may be feasible in human beings with optimization of the imaging methods.

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Distributions of 137Cs, 201Tl, 203Hg, 203Pb and 57Co in a rat hepatoma model. Comparison with 67Ga.

The distribution of carrier-free 203Pb-acetate, 203HgCl2, 57 CoCl2, 137CsCl and 201TlCl was investigated in rats bearing thigh-implanted Morris 7777 hepatomas. Viable and nonviable tumor tissue was collected in order to determine the relative affinities of the radiopharmaceuticals for these tissues. The animals were sacrificed at 4, 24, 48, 72 and 96 hrs following intravenous injection. Washout of the radioisotope from the viable tumor tissue was rapid, the maximum concentration being reached on or before 4 hrs following injection. In contrast, residual activity within the nonviable tumor tissue decreased much more slowly and in some cases even increased with time. Viable tumor-to-muscle and nonviable tumor-to-muscle ratios for 203Pb, 203Hg and 57Co were comparable to the analogous ratios reported for 67Ga. However, none of these isotopes approached 67Ga as a potential tumor imaging agent because the large ratios were the result of low muscle uptake rather than high tumor uptake. Blood clearance of 67Ga was faster than any of the five cations, while viable and nonviable tumor affinity for 67Ga was greater than for any of the radiopharmaceuticals studied.

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The effect of certain variables on the tumor and tissue distribution of tracers. Part 1; Carrier.

Buffalo rats bearing thigh-implanted strain-7777 Morris hepatomas were used as a model for studying the effect of carrier material on the body distribution, tumor uptake, excretion, and tumor-to-background ratios of 67Ga and 54Mn. An effort was also made to observe the changes in 67Ga and 54Mn concentrations induced by carrier in viable tumor and skeletal muscle, relative to their interstitial fluid space. This value is referred to as the Tissue Distribution Index. Carrier manipulation resulted in striking changes in the distribution of the two ions from the carrier-free state. The data also indicated a difference in the pharmacodynamics of 67Ga and 54Mn in malignant and healthy tissues which could be of importance to nuclear medicine and oncology.

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The effect of certain variables on the tumor and tissue distribution of tracers. II. Carrier effect: rapidity of onset and concentrations necessary for initiation and maximum response.

The smallest quantity of carrier Ga and Mn necessary to initiate and maximize a carrier effect was studied in the Morris 7777 rat hepatoma model. The quantity needed for a maximum response did not appear to adversely effect the rats. Not all tissues were equally affected at the same plasma concentrations. If carrier Ga was administered 2 hours following 67Ga injection and the rats sacrificed 30 minutes later, a dramatic change occurred in background activity, which was more pronounced in healthy than malignant tissues. Early viable and nonviable tumor/background ratios were improved by this technique. The data suggest that the use of carrier Ga and Mn might improve early lesion/background ratios in patients. This could be of use if tumor imaging were undertaken with 68Ga or 52mMn with positron detector systems.

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The effect of certain variables on the tumor and tissue distribution of tracers. III. Salicylates and vasoactive drugs.

Attempts were made to increase the viable tumor concentration of 54Mn and 67Ga in a rat hepatoma model by administering rat angiotensin, tolazoline, and salicylates. Salicylates increased the tumor concentrations of 54Mn and improved 65Mn viable tumor/background ratios. 67Ga was not affected by the salicylates. The salicylate effect appeared to be mediated by intracellular mechanisms rather than alterations in plasma protein binding. Rat angiotensin slightly increased the concentrations of 67Ga in the tumors but not enough to suggest that it would be useful clinically. Tolazoline did not increase tumor uptake of the tracers.

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The effect of certain variables on the tumor and tissue distribution of tracers. IV. False carriers: ferric citrate.

The intravenous administration of Fe+3 -citrate (1.6 mg/kg body weight) was demonstrated to alter the concentration of carrier-free 67Ga and 54Mn in malignant and healthy tissues of the rat, Morris 7777 hepatoma model. When the Fe+3 was injected 2 hours before, simultaneously with, or 2 hours after 67Ga (and the rats sacrificed 4 hours after injection), the 67Ga in most normal tissues decreased, and the viable tumor concentrations increased by 135, 24, and 47%, respectively. Twenty-four hours after a simultaneous administration of Fe+3 and 67Ga, egress of 67Ga from the tumor was much less than from the healthy tissues. These changes resulted in significant improvements in viable tumor to background ratios, especially at 4 hours. These changes induced in the distribution of the two tracers by Fe+3 indicate that some kinetic characteristics are shared. This is discussed in the light of their response to carrier Ga and Mn. The use of Fe+3 shows promise as a means of improving tumor/background ratios for 68Ga and 52mMn, two short-lived positron emitters that can be used with positron scanners. Gallium-67 imaging may also be improved by these techniques. The Fe+3 increases excretion of 67Ga from the animal, and this could result in a lower radiation dose to a patient.

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The effect of certain variables on the tumor and tissue distribution of tracers V: false carrier effect, II, Fe.

The effect of Fe3+ citrate on carrier-free 67Ga and 59Fe kinetics was studied in a Buffalo rat-Morris 7777 hepatoma model. Two mg Fe3+ citrate/Kg were administered intravenously in a variety of time sequences, prior to and following the tracers, and the rats were killed at 4 or 24 hours. 67Ga concentrations could be increased in tumor and decreased in most normal tissues. Administering Fe3+ both one half hour before and 2 hours after the tracers produced 67Ga values equivalent to 72-hour carrier-free values after 4 hours, while simultaneously decreasing gut secretion and increasing urinary excretion. The 59Fe and 67Ga kinetics suggested that events at both vascular and cellular levels were responsible for these changes. This study demonstrated the potential utility of Fe3+ citrate for improving both conventional 67Ga and positron (68Ga) imaging of tumors.

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The effect of certain variables on the tumor and tissue distribution of tracers: VI. False-carrier effect, Part III, Fe.

Previous work has shown that Fe3+, when administered in the proper dose and time sequence, increases the tumor uptake of gallium-67 (67Ga) while decreasing its uptake by normal tissues. The purpose of this series of experiments was to examine further the postulate that the false carrier effect is mediated at the cellular as well as the vascular level, determine the lowest concentration of ionic Fe3+ that will induce near maximum tumor/background ratios (T/Bkg), determine the best technique for its administration, and decide whether Benadryl and dexamethasone could be used to offset side effects of the Fe3+ without altering tumor and tissue kinetics. Fe3+ altered tissue levels of 67Ga prior to changes in the blood. The threshold for initiation of the false-carrier effect varied to some extent from one organ to another. Tumor uptake of 67Ga was either enhanced or unaltered at 4 hours after injection; 0.3 mg Fe3+/kg administered 0.5 hour before and 2 hours after the 67Ga enhanced 4-hour T/Bkg by a factor of about ten. Twenty-four-hour ratios were improved (to a lesser extent than 4-hour), but decreased concentrations of 67Ga occurred in the tumor. Dexamethasone and Benadryl did not alter the outcome of the experiment. This technique should be useful for imaging with gallium-68 and the PET camera.

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