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This study describes the synthesis and preliminary biologic evaluation of an (111)In-labeled peptide antagonist of the urokinase-type plasminogen activator receptor (uPAR) as a potential probe for assessing metastatic potential of human breast cancer in vivo. The peptide (NAc-dD-CHA-F-dS-dR-Y-L-W-S-betaAla)(2)-K-K(DOTA)-NH(2) was synthesized and conjugated with the DOTA chelating moiety via conventional solid-phase peptide synthesis (SPPS), purified by reversed-phase HPLC, and characterized by MALDI-TOF MS and receptor binding assay. In vitro receptor binding studies demonstrated an IC(50) of 240 +/- 125 nM for the peptide, compared with IC(50) values of 0.44 +/- 0.02 and 0.75 +/- 0.01 nM for the amino terminal fragment (ATF) of the urokinase-type plasminogen activator (uPA) and full-length uPA, respectively. In vivo biodistribution studies were carried out using SCID mice bearing MDA-MB-231 human breast cancer xenografts. Biodistribution data was collected at 1, 4, and 24 h postinjection of (111)In-DOTA-peptide, and compared with data obtained using a scrambled control peptide as well as with data obtained using wild-type ATF radiolabeled with I-125. Biodistribution studies showed rapid elimination of the (111)-labeled peptide from the blood pool, with 0.12 +/- 0.06% ID/g remaining in blood at 4 h pi. Elimination was seen primarily via the renal/urinary route, with 83.9 +/- 2.2% ID in the urine at the same time point. Tumor uptake at this time was 0.53 +/- 0.11% ID/g, resulting in tumor/blood and tumor/muscle ratios of 4.2 and 9.4, respectively. Uptake in tumor was significantly higher than that obtained using a scrambled control peptide that showed no specific binding to uPAR (p &lt; 0.05). In vitro and ex vivo results both suggested that the magnitude of tumor-specific binding was reduced in this model by endogenous expression of uPA. The results indicate that radiolabeled peptide uPAR antagonists may find application in the imaging and therapy of uPAR-expressing breast cancers in vivo.

bioconjugate chemistry

Synthesis and Characterization of an <sup>111</sup>In-Labeled Peptide for the in Vivo Localization of Human Cancers Expressing the Urokinase-Type Plasminogen Activator Receptor (uPAR)

Synthesis and Characterization of an 111In-Labeled Peptide for the in Vivo Localization of Human Cancers Expressing the Urokinase-Type Plasminogen Activator Receptor (uPAR)

Synthesis and Characterization of an ¹¹¹In-Labeled Peptide for the in Vivo Localization of Human Cancers Expressing the Urokinase-Type Plasminogen Activator Receptor (uPAR)