1998 Fiscal Year Final Research Report Summary
Radiopharmaceuticals that liberate radiometabolites of urinary excretion by renal brush border enzymes
| Project/Area Number |
09672279
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
ARANO Yasushi Kyoto University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (90151167)
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| Project Period (FY) |
1997 – 1998
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| Keywords | Antiby fragments / Metabilizable linkage / Targeted imaging / Radiotherapy / Radiopharmaceuticals / Radiometabilites / Brush border enzymes / Renal accumulation |
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| Research Abstract |
The renal uptake of radiolabeled low molecular weight (LMW) polypeptides presents a problem in targeted imaging and therapy. We hypothesized that the renal radioactivity levels of radiolabeled LMW polypeptides could be reduced if radiolabeled compounds of urinary excretion are released from glomerularly-filtered polypeptides before they are incorporated into renal cells by the action of brush border enzymes present on the lumen of renal tubules. 3'-[^<131>I]Iodohippuryl N^<epsilon>-maleoyl-L-lysine ([^<131>I]HML) was conjugated with a thiolated Fab fragment, since the glycyl-lysine sequence in HML is a substrate for a brush border enzyme. Fab fragments were also radiolabeled by direct radioiodination (^<125>I-Fab) or by conjugation with meta-[^<125>I]iodohippuric acid via an amide bond ([^<125>I]MPH-Fab) or an ester bond ([^<125>I]MIH-Fab) by similar procedures. When injected into mice, [^<131>I]HML-Fab demonstrated markedly low renal radioactivity levels with kidney-to-blood ratios of
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radioactivity of i from 10 min to i h due to rapid release of meta-[^<131>I]iodohippuric acid. [^<125>I]MIH-Fab and ^<125>I-Fab reached their peak ratios of 3.8 and 7.3 at 1 h, and [^<125>I]MPH-Fab showed the maximum ratio of 16.8 at 6 h. In subcellular distribution studies, both [^<125>I]MIH-Fab and ^<125>I-Fab showed radioactivity migration from the membrane to the lysosomal fraction of the renal cells from 10 to 30 min postinjection, whereas the majority of the radioactivity was detected only in the membrane fraction after administration of [^<131>I]HML-Fab at both time points. In nude mice, [^<131>I]HML-Fab showed one quarter of renal radioactivity of ^<125>I-Fab without impairing the target radioactivity levels 3 h after injection. These findings indicated that HML is a useful reagent for targeted imaging and therapy using antibody fragments as vehicles. These findings also suggested that the design of radiolabeled LMW polypeptides that liberate radiometabolites of urinary excretion by the action of brush border enzymes may constitute a new strategy for reducing the renal radioactivity levels of LMW polypeptides. Less
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