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The knob domains from the fiber proteins of adenovirus serotypes 2 and 12 were labeled with radioiodine and then injected into the bloodstreams of mice. Knob proteins with functional binding sites for the coxsackie and adenovirus receptor (CAR) were cleared rapidly from the circulation, with radioactivity appearing predominantly in the stomach, while knob mutants unable to bind to CAR remained in the blood circulation for a prolonged period. The clearance of radiolabeled wild-type knob from the blood was slowed by coinjecting an excess of unlabeled wild-type knob protein. An earlier study showed that 99m Tc-labeled knob protein with intact CAR-binding activity also cleared rapidly from the blood circulation of mice, with radioactivity accumulating predominantly in the liver (K. R. Zinn et al., Gene Ther. 5:798-808, 1998). Together these results suggest that rapid clearance of knob protein from the blood results from specific binding to CAR in the liver and that the bound knob then enters a degradative pathway. The elevated levels of radioiodine in the stomach observed in our experiments are consistent with deiodination of labeled knob by dehalogenases in hepatocyte microsomes and uptake of the resultant free radioiodine by Na/I symporters in the gastric mucosa. Although CAR has been shown to localize in tight junctions of polarized epithelial cells, where it functions in intercellular adhesion, the results of our study suggest that a subset of CAR molecules in the liver is highly accessible to ligands in the blood and able to rapidly deliver bound ligand to an intracellular degradative compartment.

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Tin-117 has certain physical characteristics (half-life of 13.6 days, low-energy-conversion electrons, gamma photon of 158.6 keV) that suggest that it may be a favorable agent for radionuclide therapy. It has been shown in animal models that Sn-117m in the chemical form Sn(4+)diethylenetriaminepentaacetic acid localizes selectively in bone. The authors therefore studied its whole-body distribution in 10 patients to obtain absorbed dose estimates for therapy. The results showed that more than 50% of the administered activity was absorbed in the bones of patients with metastatic carcinoma. Retention was determined primarily by radioactive decay. For adult men, the radiation absorbed dose estimate averaged 54.8 mGy/MBq (203 rad/mCi) to bone surfaces and 6.1 mGy/MBq (22.6 rad/mCi) to the red marrow. All other tissues received less than 1/10 of the dose received by red marrow. These results suggest that a clinical therapeutic trial should be attempted.