Noriko Sato

3D-micro-MR angiography of mice using macromolecular MR contrast agents with polyamidoamine dendrimer core with reference to their pharmacokinetic properties.

Four novel macromolecular MRI contrast agents, all of which had the same chemical composition but different molecular weights, were prepared using generation‐3, ‐4, ‐5, and ‐6 polyamidoamine (PAMAMTM) dendrimers conjugated with a bifunctional diethylenetriaminepentaacetic acid derivative to change the blood retention, tissue perfusion, and excretion. Size‐dependent changes in the pharmacokinetics were observed in the biodistribution study. 153Gd‐labeled generation‐6 PAMAMTM‐conjugates remained in the blood significantly longer than all of the other preparations (P < 0.001). The increase in blood‐to‐organ ratio of the preparations was found to correlate with increasing molecular size (P < 0.001). Additionally, 3D‐micro MR images and angiography of mice of high quality and detail were obtained using PAMAMTM‐(1B4M‐Gd)x as a macro‐molecular MRI contrast agent with a 1.5‐T clinical MRI instrument. Numerous fine vessels of ∼200 μm diameter were visualized on subtracted 3D‐MR angiographms with G6D‐(1B4M‐Gd)192. The quality of the images was sufficient to estimate the microvasculature of cancerous tissue for anti‐angiogenesis therapy and to investigate knockout mice. Magn Reson Med 45:454–460, 2001.

Pharmacokinetics and enhancement patterns of macromolecular MR contrast agents with various sizes of polyamidoamine dendrimer cores

Four macromolecular contrast agents are synthesized to visualize small vessels by MRI using generation‐3 (G3D), ‐4 (G4D), ‐5 (G5D), and ‐6 (G6D) polyamidoamine dendrimers conjugated to chelated gadolinium (Gd). The pharmacokinetics, enhancement patterns, and the ability of these constructs to visualize fine vessels is evaluated by dynamic MRI in relationship to their size. Gd‐G6D and ‐G5D exhibit a prolonged high vascular (ventricular) signal intensity (SI) with high ventricle‐to‐organ SI ratios. The initial high vascular SI with Gd‐G4D decreases to a value as low as that obtained with Gd‐G3D and Gd‐dimeglumine‐diethylenetriaminepentaacetic acid (Gd‐DTPA). Gd‐G5D, ‐G4D, and ‐G3D show high renal SIs, and Gd‐DTPA prominently enhances the skin. Gd‐G6D and ‐G5D present fine vasculature significantly more clearly than Gd‐G3D and ‐DTPA (P < 0.005). As the molecular size increases, the excretion of the 153Gd‐conjugates is retarded. In conclusion, Gd‐G6D and ‐G5D are retained in the blood and present fine vessels with high quality and detail, and should be adequate for visualizing small tumor vasculature. Magn Reson Med 46:1169–1173, 2001.

Automatic Voxel-Based Morphometry of Structural MRI by SPM8 plus Diffeomorphic Anatomic Registration Through Exponentiated Lie Algebra Improves the Diagnosis of Probable Alzheimer Disease

BACKGROUND AND PURPOSE: The necessity for structural MRI is greater than ever to both diagnose AD in its early stage and objectively evaluate its progression. We propose a new VBM-based software program for automatic detection of early specific atrophy in AD. MATERIALS AND METHODS: A target VOI was determined by group comparison of 30 patients with very mild AD and 40 age-matched healthy controls by using SPM. Then this target VOI was incorporated into a newly developed automated software program independently running on a Windows PC for VBM by using SPM8 plus DARTEL. ROC analysis was performed for discrimination of 116 other patients with AD with very mild stage (n = 45), mild stage (n = 30) and moderate-to-advanced stages (n = 41) from 40 other age-matched healthy controls by using a z score map in the target VOI. RESULTS: Medial temporal structures involving the entire region of the entorhinal cortex, hippocampus, and amygdala showed significant atrophy in the patients with very mild AD and were determined as a target VOI. When we used the severity score of atrophy in this target VOI, 91.6%, 95.8%, and 98.2% accuracies were obtained in the very mild AD, mild AD, and moderate-to-severe AD groups, respectively. In the very mild AD group, a high specificity of 97.5% with a sensitivity of 86.4% was obtained, and age at onset of AD did not influence this accuracy. CONCLUSIONS: This software program with application of SPM8 plus DARTEL to VBM provides a high performance for AD diagnosis by using MRI.

Monoclonal antibody-dendrimer conjugates enable radiolabeling of antibody with markedly high specific activity with minimal loss of immunoreactivity

Abstract. For the purpose of radioimmunotherapy, labelling of monoclonal antibody with high specific activity is often necessary, especially when using a radionuclide with a shorter half-life. Polyamine dendrimers (PAMAM) are novel synthetic polymeric molecules with large numbers of amine residues on their spherical surface. In order to bind large numbers of radiometals to single antibody molecules, the generation-4 PAMAM (G4), which has 64 amines, was conjugated with 43 molecules of 2-(p-isothiocyanatobenzyl)-6-methyl-diethylene triamine penta-acetic acid (1B4M), a derivative of DTPA. This product [G4-(1B4M)43] was then conjugated with OST7, a murine monoclonal IgG1. We evaluated the achievable specific activity for 111In labeling, immunoreactivity, biodistribution, and tumor targeting in mice of the 111In- or 153Gd-OST7-G4-(1B4M)43 as compared with radiolabeled OST7-1B4M or 56C-1B4M. The maximum specific activity of 111In-OST7-G4-(1B4M)43 and 111In-OST7-1B4M was 470 and 8.7xa0GBq/mg (12,700 and 263xa0mCi/mg), respectively. Immunoreactivity of radiolabeled OST7-G4-(1B4M)43 and OST7-1B4M, as determined by the binding to KT005 cells expressing the antigen, was respectively 91% and 84% of that of 125I-labelled OST7. Biodistribution studies for preparations with maximum specific activity in normal mice 3xa0h after injection showed that 111In- or 153Gd-OST7-G4-(1B4M)43 cleared faster from the blood and accumulated more in the liver than did 111In- or 153Gd-OST7-1B4M. The dendrimer 1B4M [G4-(1B4M)64] itself showed similar saturation effects with metals. The radioactivity in all the other organs reflected the rapid clearance of radioactivity from the blood. 153Gd-OST7-G4-(1B4M)43 showed specific accumulation in the KT005 tumor. In conclusion, we could successfully bind 49 times as many metal atoms to an antibody molecule as is possible with conventional metal labeling for indium and gadolinium, and did so with minimal loss of immunoreactivity. When we achieved radiolabeling with maximum specific activity, Gd conjugate showed better biodistribution than In conjugate.

Micro-MR angiography of normal and intratumoral vessels in mice using dedicated intravascular MR contrast agents with high generation of polyamidoamine dendrimer core: Reference to pharmacokinetic properties of dendrimer-based MR contrast agents

Pharmacokinetic characteristics of intravascular macromolecular magnetic resonance imaging (MRI) contrast agents with polyamidoamine dendrimer cores smaller than generation‐7 were previously studied in the literature. To evaluate the effects of greater hepatic uptake on the pharmacokinetics of the larger generation dendrimers, the MRI contrast agents GxD‐(1B4M‐Gd) u20092u2009x+2 were synthesized with generation‐7, ‐8, and ‐9 polyamidoamine dendrimers and 2‐(p‐isothiocyanatobenzyl)‐6‐methyl‐diethylenetriaminepentaacetic acid (1B4M). Their pharmacokinetic characteristics in mice were compared with that of G6D‐(1B4M‐Gd)256. In biodistribution and dynamic micro‐MRI studies, significantly less renal accumulation of G7D‐(1B4M‐Gd)512, G8D‐(1B4M‐Gd)1024, and G9D‐(1B4M‐Gd)2048 was shown compared to G6D‐(1B4M‐Gd)256 (P < 0.01). There was a significantly greater accumulation of G8D‐(1B4M‐Gd)1024 and G9D‐(1B4M‐Gd)2048 in the liver compared to G6D‐(1B4M‐Gd)256 and G7D‐(1B4M‐Gd)512 (P < 0.01). The highest blood retention of all dendrimer‐based MRI contrast agents was exhibited by G7D‐(1B4M‐Gd)512 (P < 0.01). The normal and intratumoral fine vessels of approximately 100 μm diameter were visualized in normal or tumor‐bearing mice by high resolution three‐dimensional‐micro‐MR angiographs with G7D‐(1B4M‐Gd)512 and G8D‐(1B4M‐Gd)1024 with good vessel‐to‐soft tissue contrast. In summary, increased accumulation in the liver with concomitant decreased uptake in the kidney was caused by increased molecular sizes of the dendrimer‐based MRI contrast agents. J. Magn. Reson. Imaging 2001;14:705–713.

3D MR angiography of intratumoral vasculature using a novel macromolecular MR contrast agent

Noninvasive methods to visualize blood flow in the intratumoral vasculature have not previously been studied. In the present study, the use of a novel intravascular MR contrast agent with a generation‐6 polyamidoamine dendrimer core (G6‐(1B4M‐Gd)192; MW: 175kD) was investigated, and the vasculature in experimental tumors was visualized using 3D MR angiography (MRA). Xenografted tumors in nude mice of two different histologies—KT005 (human osteogenic sarcoma) and LS180 (human colon carcinoma)—were used to obtain 3D MRA using G6‐(1B4M‐Gd)192 and Gd‐DTPA. The contrast MR sectional images were correlated with the corresponding histological sections. The intratumoral vasculature in the KT005 tumor was clearly visualized by 3D MRA, which became more evident with the growth of the tumor xenograft. In contrast, the intratumoral vasculature in the LS180 tumor was sparser and much less developed than that in KT005 tumors. Blood vessels with a diameter as small as 100 μm based on histology were visualized using 0.033 mmol Gd/kg of G6‐(1B4M‐Gd)192. In conclusion, intratumoral vasculature with a 100‐μm diameter was visualized better using 3D MRA with G6‐(1B4M‐Gd)192 than with Gd‐DTPA. Magn Reson Med 46:579–585, 2001.

Novel intravascular macromolecular MRI contrast agent with generation-4 polyamidoamine dendrimer core: Accelerated renal excretion with coinjection of lysine

One of the major limitations to macromolecular MRI contrast agents (MRI‐CAs) is their slow clearance and associated decreased excretion of gadolinium (Gd(III)). The effect of coinjecting lysine to accelerate renal excretion of a macromolecular MRI‐CA (generation‐4 PAMAM™ dendrimer (G4D‐(1B4M‐Gd)64)) was investigated. The biodistribution and urine and fecal excretion in athymic mice was evaluated with and without lysine coinjection. 3D‐dynamic‐micro‐MRI with G4D‐(1B4M‐Gd)64 was obtained with and without lysine coinjection, and the serial signal intensity (SI) change in the blood and organs was evaluated. When lysine was coinjected, urinary excretion of G4D‐(1B4M‐Gd)64 increased 5.4‐fold compared to that without lysine, resulting in decreased renal accumulation of G4D‐(1B4M‐Gd)64 from 150% to 40% injected dose per gram (P < 0.001). On dynamic MRI with G4D‐(1B4M‐Gd)64, when lysine was coinjected, the kidney‐to‐blood SI ratio was significantly lower than that obtained without lysine (P < 0.001). When lysine was coinjected, the G4D‐(1B4M‐Gd)64 was excreted from the kidney intact. Magn Reson Med 46:457–464, 2001.

Autoimmune pancreatitis with F-18 fluoro-2-deoxy-D-glucose PET findings

Two cases of pancreatitis induced by autoimmunity with PET images using F-18 fluoro-2-deoxy-D-glucose (FDG) are reported. The patients had abdominal pain and were thought to have possible pancreatic neoplasms. In one patient, PET showed intense uptake of the entire pancreas, but a Ga-67 scan yielded a negative result. Because the serum immunoglobulin G level was high, autoimmune pancreatitis was diagnosed in this patient. He underwent steroid therapy and fully recovered. In another patient with positive antinuclear antibodies and hyperglobulinemia, focal intense uptake was found in the head of the pancreas on the FDG PET. She also recovered with steroid therapy. Autoimmune pancreatitis is a relatively new form of chronic pancreatitis and should be kept in mind when making a differential diagnosis of pancreatic cancer with the assistance of FDG PET.

Differential Uptake of 18F-fluorodeoxyglucose by Experimental Tumors Xenografted into Immunocompetent and Immunodeficient Mice and the Effect of Immunomodification

PURPOSEnTo study the contribution of immunologic background to the uptake of fluorine-18-fluorodeoxyglucose ((18)F-FDG) by the tumor tissues.nnnMETHODSnThe uptakes of (18)F-FDG to the same experimental tumor model (SCCVII) xenografted into immunocompetent and immunodeficient (athymic) mice were compared. In addition, the immunomodifying effect of steroid on the uptake of (18)F-FDG by these tumors was investigated.nnnRESULTSnThe uptake of (18)F-FDG by the tumors in immunocompetent mice was significantly higher than that in immunodeficient (athymic) mice. Although steroid pretreatment had no effect on the tumor uptake in immunodeficient mice, it significantly decreased the tumor uptake in immunocompetent mice.nnnCONCLUSIONnThe higher tumor uptake of (18)F-FDG observed in immunocompetent mice, modulated by steroid pretreatment, was contributed by the host immune reaction, probably cellular immunity employed by T-lymphocytes. These findings can clinically conclude that the intense accumulation of (18)F-FDG in the metastatic lymph nodes, which contain only a small number of cancer cells, was caused by the enhanced uptake of (18)F-FDG by activated T-lymphocytes due to host immunity against cancer cells present in metastatic lymph nodes.

Three-Step Tumor Imaging with Biotinylated Monoclonal Antibody, Streptavidin and 111In-DTPA–Biotin

The purpose of this study was to test the three-step targeting of tumors in mice using biotinylated antibody, streptavidin and radiolabeled biotin. Nude mice bearing subcutaneous LS180 human colon cancer xenografts were intravenously administered with 200 microg of the biotinylated anti-Tn monoclonal antibody MLS128, and 2 days later they got intravenous injection of 50 microg of streptavidin. They were intravenously injected 1, 4 or 7 days later with 0.5 microg of 111In-diethylenetriamine pentaacetic acid (DTPA)-biotin. The tumor uptake, determined 2 h later, was 1.4, 0.5 and 0.6% injected dose/gram of tissue (ID/g), respectively, and the blood radioactivity was 1.0, 0.2 and 0.2% ID/g, respectively. When the interval between the streptavidin and radiolabeled biotin injections was prolonged from 1 day to 7 days, the tumor-to-blood ratio 2 h after injection of 111In-labeled biotin increased from 1.5 to 4.0. Clear tumor images were obtained as early as 2 h after injection of radiolabeled biotin. In conclusion, these preliminary data suggested that the three-step method using the streptavidin-biotin system would be applicable in an experimental mouse tumor model and provides images of tumors rapidly and clearly after injection of radiolabeled biotin.