The overall purpose of this research was to improve the tumor targeting properties of radiolabeled biologicals by optimizing chemical parameters. This year we have investigated the methods of radiolabeling a peptidomimetic integrin alphaVbeta3 antagonist, 4-[2-(3,4,5,6-tetrahydro-pyrimidine-2-ylamino)ethyloxy]benzoyl-2-(S)-aminoethylsulfonyl-amino-beta-alanine (IA) with In-111 and Tc-99m(CO)3 for the assessment of tumor angiogenesis and receptor status in tumor. IA conjugated with an aminodiacetic acid and labeled with Tc-99m(CO)3, and IA conjugated with isothiocyanatobenzyl-DOTA and labeled with In-111 were tested for the receptor targeting properties in nude mice bearing receptor-positive tumor. The In-111 IA was excreted via the renal system whereas the Tc-99m IA was taken up rapidly by the hepatobiliary system that resulted in a lower Tc-99m IA concentration in blood. The In-111 IA accumulation in the receptor-positive tumor was greater than the Tc-99m IA. The tumor uptake of both In-111 IA and Tc-99m IA was blocked by co-administration of a molar excess amount of unlabeled IA, indicating that the tumor uptake was receptor mediated. However, the tumor to organ ratios did not improve much over time because the labeled IAs were not retained well in the tumor perhaps due to a low affinity to the receptor. This study helped us identify two parameters to improve: 1) the receptor-binding affinity needs to be improved. 2) whole-body clearance pharmacokinetics needs to be optimized by preventing rapid hepatobiliary clearance. To improve the receptor targeting properties, we are now investigating the use of macromolecules as universal carriers of IA and radioisotopes for cancer diagnosis and therapy.
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