Integrins are a family of cell surface heterodimeric glycoproteins that mediate diverse biological events involving cell-cell and cell-matrix interactions (1). They consist of an α and a β subunit and are important for cell adhesion and signal transduction. The αvβ3 integrin is the most prominent receptor class affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). The αvβ3 integrin is strongly expressed on tumor cells, activated endothelial cells (3), and arterial smooth muscle cells (8). In contrast, expression of αvβ3 integrin is weak on resting endothelial cells and most normal tissues. The αvβ3 antagonists are being studied as anti-tumor and anti-angiogenic agents (4, 9, 10), and the agonists are being studied as angiogenic agents for coronary angiogenesis (11, 12). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) was identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins including αvβ3. Various radiolabeled antagonists and peptides were introduced for imaging of tumors and tumor angiogenesis (13).
TA138, an antagonist to the αvβ3 integrin, was developed based on SH066 (a quinolone-based vitronectin receptor antagonist) (14). TA138 contains a DOTA moiety for 111In labeling. 111In-TA138 (RP748) was found to have a high accumulation in a spontaneous mammary adenocarcinoma (αvβ3-positive) in the c-Neu Oncomouse model (14, 15). The binding of 111In-TA138 to the integrin receptor was found to be specific both in vitro and in vivo.
A detailed chemical synthesis of TA138 (3-sulfon-N-[[4,7,10-tris(carboxymethyl)1,4,7,10-tetraazacyclododec-1-yl]acetyl]-l-alanyl-N-[2-[4-[[[(1S)-1-carboxy-2[[[1,4-dihydro-7-[(1H-imidazol-2-ylamino]methyl]-1-methyl-4-oxo-3-quinolinyl]carbonyl]amino]ethyl]amino]-sulfonyl]-3,5-dimethylphenoxy]-1-oxobutyl]amino]ethyl]-3-sulfo-l-alaninamide) was reported by Liu et al. (16). 111InCl3 solution (81.4 MBq, 2.2 mCi) was added to a solution of TA138 (100 μg) in ammonium acetate buffer (17). The mixture was heated at 100ºC for 5 min. The radiochemical purity of 111In-TA138 was 98% as measured by high-performance liquid chromatography (HPLC). The specific activity was 0.83 MBq/μg (22.5 μCi/μg).
In Vitro Studies: Testing in Cells and Tissues
TA138 and SH066 were shown to inhibit αvβ3-mediated binding of β3-transfected 293 human embryonic kidney cells with an IC50 of 12 ± 3 and 11 ± 3 nm, respectively (17). Neither compound inhibited αIIbβ3, αvβ5, and α5β1 integrin in cell-based binding assays. TA138 and RP748 were reported to be effective in inhibiting αvβ3-mediated adhesion of human endothelial cells to fibrinogen with an IC50 of 40 ± 1 and 42 ± 1 nm, respectively (18). In a chick chorioallantoic membrane model, TA138 (2 μg/ml) inhibited basic fibroblast growth factor-induced neovascularization by 50%. Activation of endothelial cells in culture by Mn2+ led to a 17-fold increase in 111In-TA138 binding affinity (Kd) for αvβ3 integrin from 374 nm to 21 nm and a 0.8-fold (Bmax) increase in binding sites/cell from 130,000 sites/cell to 230,000 sites/cell (11).
Biodistribution studies of 111In-TA138 were evaluated in the c-Neu Oncomouse spontaneous mammary tumor model (17). Whole-body small animal images by dynamic scintigraphy were obtained at 0.5, 1, and 2 h after injection of 111In-TA138 (74 MBq/kg, 2 mCi/kg). The tumor uptake of 111In-TA138 was visible at all time points. Tissue distribution of the tracer was studied at 2 and 24 h. 111In-TA138 showed high uptake of 9.4% injected dose (ID)/g in the tumor at 2 h and decreased to 3.5% ID/g at 24 h. 111In-TA138 was cleared rapidly from the blood with an initial half-life of 1.1 h. The non-targeted organ with the highest uptake was the uterus (4.71% ID/g), followed by the colon (3.84%), lung (2.74%), kidney (2.33%), stomach (2.23%), and liver (1.94%) at 2 h after injection. Very high radioactivity was found in the urine, indicating high renal excretion. There was a dose-dependent decrease in 111In-TA138 tumor uptake with increasing doses of TA138 (300-2100 μg/m2). Tumor accumulation was 8.3% ID/g and 1.8% ID/g when the TA138 dose was 0 and 2100 μg/m2, respectively. In a separate study, 90Y-TA138 uptake in the tumor and other organs was similar to 111In-TA138 in the c-Neu Oncomouse model (15). Therefore, 90Y-TA138 can be developed as a radiopharmaceutical for tumor treatment, and 111In-TA138 can be developed as an imaging agent for tumor detection.
111In-TA138 was able to detect vascular remodeling in apolipoprotein E-negative (apoE−/−) mice with left common carotid artery injury (11). There was a significantly higher uptake of 111In-TA138 in the injured artery than in the contralateral uninjured artery. A 50-fold excess of unlabeled TA138 decreased 111In-TA138 uptake by 72%, demonstrating specificity of accumulation of radioactivity. Immunohistochemical studies confirmed an increase in expression of αvβ3 integrin in the injured arteries. There was also an increase in proliferation of vascular cells in the injured arteries.
Other Non-Primate Mammals
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Created: October 17, 2005; Last Update: March 11, 2011.
National Center for Biotechnology Information (US), Bethesda (MD)
Leung K. 111In-TA138. 2005 Oct 17 [Updated 2011 Mar 11]. In: Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.