Distribution and pharmacokinetic analysis of angiostatin radioiodine labeled with high stability.
OBJECTIVE
Radiotracers of anticancer agents provide important information on its in vivo handling. Angiostatin (AST) is a promising anticancer drug with potent antiangiogenic effects, but reported AST radiotracers suffer from poor in vivo stability. In this study, we synthesized an AST probe radioiodinated via the Bolton-Hunter reagent (125I-BH-AST) and investigated its stability and biokinetics in mice.


METHODS
125I-BH-AST and conventional direct radioiodinated 125I-AST were evaluated for human endothelial cell binding characteristics. In vivo stability of the radiotracers was compared by biodistribution studies in normal ICR mice. Angiostatin pharmacokinetics was analyzed by serial blood sampling after intravenous injection of 125I-BH-AST with varying AST concentrations in mice.


RESULTS
Both 125I-AST and 125I-BH-AST retained selective endothelial binding as demonstrated by dose-dependent inhibition by nonradiolabeled AST. 125I-BH-AST was substantially more stable in mice than 125I-AST, with 28- and 7-fold lower 24-h thyroid and blood activities, respectively (15.5+/-1.5 vs. 430.9+/-32.2 and 0.1+/-0.0 vs. 0.8+/-0.0 %ID/g; both P<.005). Using (125)I-BH-AST, we found that 24-h AST accumulation was highest in the kidneys, followed by the liver and lungs. Kinetic analysis of 125I-BH-AST revealed AST to have linear pharmacokinetics with a T(1/2) of 5.8+/-2.6 h, volume of distribution (V(d)) of 6.8+/-1.3 ml and clearance of 0.8+/-0.1 ml/h.


CONCLUSIONS
Radioiodine-labeled AST prepared by the BH method provides a radioprobe with superior stability and improved in vivo biokinetics that is useful for distribution and pharmacokinetic studies.
Song
Sung Hee
SH
Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, South Korea.
Jung
Kyung-Ho
KH
Paik
Jin-Young
JY
Koh
Bong-Ho
BH
Bae
Joon-Sang
JS
Choe
Yearn Seong
YS
Lee
Kyung-Han
KH
Kim
Byung-Tae
BT
D043168:Angiostatins / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D002478:Cells, Cultured; D004355:Drug Stability; D042783:Endothelial Cells / Q000000981:diagnostic imaging* / Q000378:metabolism*; D006801:Humans; D008657:Metabolic Clearance Rate; D051379:Mice; D008813:Mice, Inbred ICR; D009928:Organ Specificity; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013388:Succinimides / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D019275:Radiopharmaceuticals; D013388:Succinimides; C022581:Bolton-Hunter reagent; D043168:Angiostatins