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

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• 作者：Masahiro Ono ; Yasushi Arano ; Tomoya Uehara ; Yasushi Fujioka ; Kazuma Ogawa ; Shinji Namba ; Takahiro Mukai ; Morio Nakayama ; and Hideo Saji
• 刊名：Bioconjugate Chemistry
• 出版年：1999
• 出版时间：May 1999
• 年：1999
• 卷：10
• 期：3
• 页码：386 - 394
• 全文大小：121K
• 年卷期：v.10,no.3(May 1999)
• ISSN：1520-4812

文摘

Hydrazino nicotinate (HYNIC) has been shown to produce technetium-99m (^99mTc)-labeled proteinsand peptides of high stability with high specific activities. However, persistent localization ofradioactivity 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 theradiopharmaceuticals. Since lysosomes are the principal sites of intracellular catabolism of proteinsand peptides, ^99mTc-HYNIC-labeled galactosyl-neoglycoalbumin (NGA) was prepared using tricineas a co-ligand to investigate the fate of the radiolabel after lysosomal proteolysis in hepatocytes. Wheninjected into mice, over 90% of the injected radioactivity was accumulated in the liver after 10 mininjection. 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 radioactivitypeak ranging from molecular masses of 0.5-50 kDa. RP-HPLC analyses of liver homogenates suggestedthe presence of multiple radiolabeled species. However, most of the radioactivity migrated to lowermolecular weight fractions on size-exclusion HPLC after treatment of the liver homogenates withsodium triphenylphosphine-3-monosulfonate (TPPMS). The TPPMS-treated liver homogenates showeda 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 thatthe chemical bonding between ^99mTc and HYNIC remains stable in the lysosomes and followingexcretion from the body. The persistent localization of radioactivity in the liver could be attributed tothe slow elimination rate of the final radiometabolite, [[^99mTc](HYNIC-lysine)(tricine)₂], fromlysosomes, and subsequent dissociation of one of the tricine co-ligands in the low pH environment ofthe 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 ofpreserving stable bonding with the Tc center is essential to reduce the residence time of radioactivityin nontarget tissues after administration of [^99mTc]HYNIC-labeled proteins and peptides.