Genetic Marker Patterns and Endogenous Mammary Tumor Virus Genes in Inbred Mouse Strains of Japan

Imai, Shunsuke; Morimoto, Junji; Tsubura, Yoshihiko; Esaki, Kozaburo; Holmes, Roger S.; Deimling, Otto von; Hilgers, J.

doi:10.1538/expanim1978.35.3_263

Cited by 28 publications

(15 citation statements)

References 44 publications

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“…Aliquots of 2 mL of [ 131 I]- l -HML-NGA were mixed with the same volume of [ 125 I]MIH-NGA, [ 125 I]MPH-NGA, [ 125 I]- d -HML-NGA, or [ 125 I]- l -HML-IT-NGA prior to administration. Biodistribution of radioactivity was determined after intravenous administration of each mixture to 6-week-old ddY male mice . Groups of five mice, each receiving 9 μg of radioiodinated NGA, were sacrificed at 5, 15, and 30 min, 1 and 3 h postinjection.…”

Section: Methodsmentioning

confidence: 99%

A Novel Radioiodination Reagent for Protein Radiopharmaceuticals with l-Lysine as a Plasma-Stable Metabolizable Linkage To Liberate m-Iodohippuric Acid after Lysosomal Proteolysis

et al. 1997

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Radiochemical design of polypeptides using metabolizable linkages would be attractive to enhance target-selective localization of radioactivity for diagnostic and therapeutic nuclear medicine. However, while use of ester bonds as the linkage allows selective release of the designed radiometabolite from covalently conjugated polypeptides after lysosomal proteolysis in nontarget tissues, low plasma stability of ester bonds causes a decrease in radioactivity levels of the target. In pursuit of new metabolizable linkages that provide stable attachment of radiolabels with polypeptide in plasma while facilitating rapid and selective release of designed radiometabolites of rapid urinary excretion in lysosomes, a new radioiodination reagent with L-lysine as the metabolizable linkage to liberate m-iodohippuric acid (L-HML) was designed and synthesized. Stabilities of the metabolizable linkage in serum and cleavabilities of the linkage in lysosomal proteolysis in hepatic cells were investigated after conjugation of [131I]-L-HML with galactosyl-neoglycoalbumin (NGA). For comparison, a radioiodination reagent with an ester bond to release m-iodohippuric acid (MIH) was conjugated with NGA under similar conditions. When incubated in human serum, [131I]-L-HML-NGA liberated less than 3% of the initial radioactivity after 24 h, whereas [125I]MIH-NGA released more than 60% of its radioactivity during the same interval. In biodistribution studies, [131I]-L-HML-NGA demonstrated radioactivity elimination from murine liver at a rate and excretion route similar to [125I]MIH-NGA. Analyses of murine urine after injection of [131I]-L-HML-NGA indicated a single radioactivity peak at fractions identical to those of m-iodohippuric acid. Biodistribution studies of radioiodinated NGAs with D-lysine or cadaverine as the linkages demonstrated a delayed elimination rate from murine liver with significantly higher radioactivity being excreted in the feces at 24 h postinjection. Thus, L-HML is the first reagent that allows stable attachment of radiolabel with polypeptide in serum while facilitating selective release of a radiometabolite with rapid urinary excretion from covalently conjugated polypeptides after lysosomal proteolysis at a rate similar to that of ester bonds. Thus, L-HML is potentially useful for the radioiodination of polypeptides for diagnostic and therapeutic purposes.

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Section: Methodsmentioning

confidence: 99%

A Novel Radioiodination Reagent for Protein Radiopharmaceuticals with l-Lysine as a Plasma-Stable Metabolizable Linkage To Liberate m-Iodohippuric Acid after Lysosomal Proteolysis

et al. 1997

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“…The protein concentration of [[ 99m -Tc](HYNIC-NGA)(tricine) 2 ] was adjusted to 90 µg/mL with saline. Biodistribution studies were performed by the intravenous administration of [[ 99m Tc](HYNIC-NGA)-(tricine) 2 ] to 6-week-old male ddY mice (27-30 g) (38). Groups of five mice each were administered 9 µg (37-56 KBq) of [[ 99m Tc](HYNIC-NGA)(tricine) 2 ] prior to sacrificing the animals at 10 and 30 min and 1, 3, 6, and 24 h postinjection by decapitation.…”

Section: Plasma Stability Of [[ 99m Tc](hynic-nga)(tricine) 2 ] [[ 99mmentioning

confidence: 99%

Intracellular Metabolic Fate of Radioactivity after Injection of Technetium-99m-Labeled Hydrazino Nicotinamide Derivatized Proteins

Ono¹,

Arano²,

Uehara³

et al. 1999

Bioconjugate Chem.

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Hydrazino nicotinate (HYNIC) has been shown to produce technetium-99m (99mTc)-labeled proteins and peptides of high stability with high specific activities. However, persistent localization of radioactivity was observed in nontarget tissues such as the liver and kidney after administration of [99mTc]HYNIC-labeled proteins and peptides, which compromises the diagnostic accuracy of the radiopharmaceuticals. Since lysosomes are the principal sites of intracellular catabolism of proteins and peptides, 99mTc-HYNIC-labeled galactosyl-neoglycoalbumin (NGA) was prepared using tricine as a co-ligand to investigate the fate of the radiolabel after lysosomal proteolysis in hepatocytes. When injected into mice, over 90% of the injected radioactivity was accumulated in the liver after 10 min injection. At 24 h postinjection, ca. 40% of the injected radioactivity still remained in liver lysosomes. Size-exclusion HPLC analyses of liver homogenates at 24 h postinjection showed a broad radioactivity peak ranging from molecular masses of 0.5-50 kDa. RP-HPLC analyses of liver homogenates suggested the presence of multiple radiolabeled species. However, most of the radioactivity migrated to lower molecular weight fractions on size-exclusion HPLC after treatment of the liver homogenates with sodium triphenylphosphine-3-monosulfonate (TPPMS). The TPPMS-treated liver homogenates showed a major peak at a retention time similar to that of [[99mTc](HYNIC-lysine)(tricine)(TPPMS)] on RP-HPLC. Similar results were obtained with urine and fecal samples. These findings suggested that the chemical bonding between 99mTc and HYNIC remains stable in the lysosomes and following excretion from the body. The persistent localization of radioactivity in the liver could be attributed to the slow elimination rate of the final radiometabolite, [[99mTc](HYNIC-lysine)(tricine)2], from lysosomes, and subsequent dissociation of one of the tricine co-ligands in the low pH environment of the lysosomes in the absence of excess co-ligands, followed by binding proteins present in the organelles. The findings in this study also suggested that the development of appropriate co-ligands capable of preserving stable bonding with the Tc center is essential to reduce the residence time of radioactivity in nontarget tissues after administration of [99mTc]HYNIC-labeled proteins and peptides.

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“…Animal studies were conducted in accordance with our institutional guidelines and approved by the Chiba University Animal Care Committee. Six-week-old male ddY mice 35 (Japan SLC Inc., Shizuoka, Japan) were injected via the tail vein with RP-HPLC purified [ 99m Tc]Tc-MAG 3 -Gly. At 10, 30 min, and 1, 3, and 6 h postinjection, the animals were sacrificed, and the organs of interest were removed, weighed, and the radioactivity counts were determined with an autowell gamma counter (Wizard 3).…”

mentioning

confidence: 99%

Renal Handling of ^99mTc-Labeled Antibody Fab Fragments with a Linkage Cleavable by Enzymes on Brush Border Membrane

et al. 2020

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The high and persistent renal radioactivity levels after injection of radiolabeled low-molecular-weight polypeptides constitute a significant problem for their diagnostic and therapeutic applications, especially when they are labeled with metallic radionuclides. To improve the renal radioactivity levels of technetium-99m ( 99m Tc)-labeled Fab fragments, a mercaptoacetyltriglycine (MAG 3 )-based new bifunctional chelating agent with a cleavable glycyl-phenylalanyl-lysine (GFK) linkage, MAG 3 -GFK-suc-TFP, was designed, synthesized, and evaluated. 99m Tc-labeled Fab was obtained by reacting MAG 3 -GFK-Fab conjugate with 99m Tc-glucarate. The GFK linkage remained stable in plasma but was cleaved by enzymes on the renal brush border membrane. The comparative biodistribution studies with indium-111 ( 111 In)-labeled Fab using SCN-CHX-A″-DTPA showed that while both radiolabeled Fabs exhibited similar elimination rates from the blood, [ 99m Tc]Tc-MAG 3 -GFK-Fab registered much lower renal radioactivity levels from 30 min post-injection onward due to the release and subsequent urinary excretion of [ 99m Tc]Tc-MAG 3 -Gly. However, [ 99m Tc]Tc-MAG 3 -GFK-Fab showed an increase in the intestinal radioactivity levels with the time that was not observed with 111 In-labeled Fab. The analysis of the intestinal contents suggested the redistribution of [ 99m Tc]Tc-MAG 3 -Gly to the intestine. The retrospective comparison of [ 99m Tc]Tc-MAG 3 -GFK-Fab with the radiolabeled Fabs so far prepared under the identical concept suggested that some portion of [ 99m Tc]Tc-MAG 3 -Gly was generated after the coated vesicle formation and they were excreted into the blood, and subsequently redistributed in the intestine via hepatobiliary excretion. In conclusion, MAG 3 -GFK-suc-TFP provided 99m Tc-labeled Fabs that exhibit low renal radioactivity shortly after injection by the postlabeling procedure. The present study indicated that, contrary to our earlier proposal, the generation of the radiometabolites would proceed not only during the internalization process of the parental antibody fragments but also after coated vesicle formation. This study also showed that the intracellular behaviors of radiometabolites played crucial roles in the elimination rates and the routes of the radioactivity from the kidney.

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Genetic Marker Patterns and Endogenous Mammary Tumor Virus Genes in Inbred Mouse Strains of Japan

Cited by 28 publications

References 44 publications

A Novel Radioiodination Reagent for Protein Radiopharmaceuticals with l-Lysine as a Plasma-Stable Metabolizable Linkage To Liberate m-Iodohippuric Acid after Lysosomal Proteolysis

A Novel Radioiodination Reagent for Protein Radiopharmaceuticals with l-Lysine as a Plasma-Stable Metabolizable Linkage To Liberate m-Iodohippuric Acid after Lysosomal Proteolysis

Intracellular Metabolic Fate of Radioactivity after Injection of Technetium-99m-Labeled Hydrazino Nicotinamide Derivatized Proteins

Renal Handling of ^99mTc-Labeled Antibody Fab Fragments with a Linkage Cleavable by Enzymes on Brush Border Membrane

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Genetic Marker Patterns and Endogenous Mammary Tumor Virus Genes in Inbred Mouse Strains of Japan

Cited by 28 publications

References 44 publications

A Novel Radioiodination Reagent for Protein Radiopharmaceuticals with l-Lysine as a Plasma-Stable Metabolizable Linkage To Liberate m-Iodohippuric Acid after Lysosomal Proteolysis

A Novel Radioiodination Reagent for Protein Radiopharmaceuticals with l-Lysine as a Plasma-Stable Metabolizable Linkage To Liberate m-Iodohippuric Acid after Lysosomal Proteolysis

Intracellular Metabolic Fate of Radioactivity after Injection of Technetium-99m-Labeled Hydrazino Nicotinamide Derivatized Proteins

Renal Handling of 99mTc-Labeled Antibody Fab Fragments with a Linkage Cleavable by Enzymes on Brush Border Membrane

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Renal Handling of ^99mTc-Labeled Antibody Fab Fragments with a Linkage Cleavable by Enzymes on Brush Border Membrane