Radiolabeled metabolites of proteins play a critical role in radioactivity elimination from the liver

Arano, Yasushi; Mukai, Takahiro; Akizawa, Hiromichi; Uezono, Takumi; Motonari, Hiroshi; Wakisaka, Kouji; Kairiyama, Claudia; Yokoyama, Akira

doi:10.1016/0969-8051(95)00009-m

Cited by 40 publications

(41 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, several other modifications of these BCAs have been investigated to improve labeling efficiency and in vivo stability. [5][6][7][8] When internalized by cells, these proteins undergo intracellular catabolism with subsequent formation of radiolabeled metabolites. In particular, after endocytotic internalization, the ligand is delivered to the endosome and then to the lysosome.…”

Section: Introductionmentioning

confidence: 99%

Disposition of radioactivity after injection of liver-targeted proteins labeled with 111In or 125I. Effect of labeling on distribution and excretion of radioactivity in rats

Štaud

Nishikawa

Morimoto

et al. 1999

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

The effect of radiolabeling liver-specific proteins on the in vivo disposition of radioactivity was investigated. The suitability of 111In and 125I as radiolabels for protein disposition studies in vivo was examined. Galactosylated and cationized bovine serum albumin were labeled with either 125I by the chloramine-T method or 111In, using 1-(4-isothiocyanatobenzyl)ethylenediaminetetraacetic acid (SCN-BZ-EDTA) or diethylenetriaminepentaacetic acid (DTPA) as bifunctional chelating agents (BCAs) and administered intravenously to rats. 125I radioactivity disappeared rapidly from the liver with subsequent excretion in the urine and bile, mainly in the TCA soluble fraction. 111In-associated radioactivity, on the other hand, remained in the hepatic tissue in considerably higher amounts during the experiment and was excreted in the bile and urine to a lower extent when compared with 125I. When the effect of BCA on excretion of 111In radioactivity was compared, no significant differences were observed in the urinary clearances. However, biliary excretion was significantly higher for 111In-SCN-BZ-EDTA-bound radioactivity. In conclusion, when compared with 125I, 111In labeling seems to more accurately characterize the in vivo distribution of liver-targeted proteins after their iv administration in rats and allows a more accurate pharmacokinetic evaluation to be performed.

show abstract

Section: Introductionmentioning

confidence: 99%

Disposition of radioactivity after injection of liver-targeted proteins labeled with 111In or 125I. Effect of labeling on distribution and excretion of radioactivity in rats

Štaud

Nishikawa

Morimoto

et al. 1999

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

show abstract

“…99m Tc-GSA has been used clinically as an ASGP-R-binding radiopharmaceutical in Japan since 1992. The derivates of glycoprotein radiolabeled with 99m Tc (8)(9)(10)(11), 125 I/ 131 I (12), and 111 In (13) have been reported for SPECT applications. 68 Ga-deferoxamine-neogalactosylalbumin (14) and 18 F-fluorobenzoate galactosyl-neoglycoalbumin (15) were introduced as PET agents.…”

mentioning

confidence: 99%

Copolymer-Based Hepatocyte Asialoglycoprotein Receptor Targeting Agent for SPECT

Yang

Mou²,

Shao³

et al. 2011

J Nucl Med

View full text Add to dashboard Cite

Poly(vinylbenzyl-O-b-D-galactopyranosyl-D-gluconamide) (PVLA) can be specifically internalized by hepatocytes via the asialoglycoprotein receptor. In this study, we synthesized and characterized galactose-carrying copolymers with hydrazinonicotinamide chains as bifunctional groups to radiolabel PVLA with 99m Tc for SPECT targeting specific hepatocytes. Methods:The copolymer was labeled with 99m Tc using tricine as a coligand. Then 99m Tc[P(VLA-co-VNI)](tricine) 2 was evaluated by in vivo metabolic stability and biodistribution in normal mice. SPECT was performed in normal New Zealand White rabbits and rabbits with liver cancer. Results: 99m Tc[P(VLA-co-VNI)](tricine) 2 was prepared in high labeling yield (.95%) and radiochemical purity (.99%), with good stability. The results of biodistribution in mice demonstrated that the liver uptake was 125.33 6 10.99 percentage injected dose per gram at 10 min after injection and could be blocked significantly by preinjecting free neogalactosylalbumin or P(VLA-co-VNI). SPECT images with high quality were obtained at 15, 30, 60, and 120 min after injection of the radiotracer. Significant radioactivity defect was observed in the liver cancer model. Conclusion: The bifunctional coupling agent hydrazinonicotinamide was introduced to PVLA via copolymerization and labeled with 99m Tc. The promising biologic properties of 99m Tc[P(VLA-co-VNI)](tricine) 2 afford potential applications for the assessment of hepatocyte function in the future.

show abstract

“…Use of NGA provides explicit information regarding the fate of radioactivity after lysosomal proteolysis in hepatocytes without being aOE ected by transchelation of radiolabels in plasma or a redistribution of radiometabolites generated elsewhere in the body to the liver (Arano et al 1994a(Arano et al , 1995Mukai et al 1999aMukai et al , 1999b. Figure 4 shows the radioactivity pro® les in the liver and blood after injection of 111 In-DOTA-NGA and 111 In-DTPA-NGA into mice.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, we used a typical serum protein, HSA, as a model. NGA is a useful polypeptide to estimate the behaviour of radiometabolites generated after lysosomal proteolysis in hepatocytes (Arano et al 1994a(Arano et al , 1995Mukai et al 1999a, b), and so this protein was used for evaluation of the residence time of the radioactivity derived from 111 In-DOTA labels in the catabolic site. In addition, the number of chelators attached per molecule of protein plays a critical role in radiochemical yields with 111 In.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of a monoreactive DOTA derivative for indium-111-based residualizing label to estimate protein pharmacokinetics

Mukai

Namba

Arano

et al. 2002

Journal of Pharmacy and Pharmacology

Self Cite

View full text Add to dashboard Cite

The purpose of this study was to develop an indium-111 (111In)-based residualizing label for estimating the pharmacokinetics of proteins. 1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), which produced a highly stable and hydrophilic 111In chelate, was selected as the chelating site, and the monoreactive DOTA derivative with a tetrafluorophenyl group as the protein binding site (mDOTA) was designed to avoid cross-linkings of proteins. mDOTA was synthesized with an overall yield of 11%. The stability in murine plasma, the radioactivity retention in the catabolic sites of proteins and the radiochemical yields of 111In-labelled proteins via mDOTA were investigated using human serum albumin (HSA), galactosyl-neoglycoalbumin (NGA) and cytochrome c (cyt c) as model proteins. 111In-labelled HSA via mDOTA was highly stable for 5 days after incubation in murine plasma. Long retention of radioactivity in the catabolic sites was observed after injection of 111In-DOTA-NGA in mice, due to the slow elimination of the radiometabolite from the lysosome. At a chelator concentration of 42.2 microM, 111In-DOTA-cyt c was produced with over 91% radiochemical yield. On the other hand, 111In-DOTA-lysine and 111In-DOTA were obtained with high radiochemical yields at lower chelator concentrations. These findings indicated that mDOTA would be an appropriate 111In-labelling agent for estimating protein pharmacokinetics. These findings also suggested that the introduction of a protein binding site at a position distal from the unmodified DOTA structure would be preferable to preparing 111In-DOTA-labelled proteins with higher specific activity.

show abstract

Radiolabeled metabolites of proteins play a critical role in radioactivity elimination from the liver

Cited by 40 publications

References 15 publications

Disposition of radioactivity after injection of liver-targeted proteins labeled with 111In or 125I. Effect of labeling on distribution and excretion of radioactivity in rats

Disposition of radioactivity after injection of liver-targeted proteins labeled with 111In or 125I. Effect of labeling on distribution and excretion of radioactivity in rats

Copolymer-Based Hepatocyte Asialoglycoprotein Receptor Targeting Agent for SPECT

Synthesis and evaluation of a monoreactive DOTA derivative for indium-111-based residualizing label to estimate protein pharmacokinetics

Contact Info

Product

Resources

About