Bivalent Approach for Homodimeric Estradiol Based Ligand: Synthesis and Evaluation for Targeted Theranosis of ER(+) Breast Carcinomas

The synthesis of estradiol based bivalent ligand [(EST)(2)DT] is reported and its potential for targeted imaging and therapy of ER(+) tumors has been evaluated. For the purpose, ethinylestradiol was functionalized with an azidoethyl-amine moiety via click chemistry. The resultant derivative was reacted in a bivalent mode with DTPA-dianhydride to form the multicoordinate chelating agent, (EST)(2)DT which displayed capability to bind Tc-99m. The radiolabeled complex, Tc-99m-(EST)(2)DT was obtained in >99% radiochemical purity and 20-48 GBq/mu mol of specific activity. RBA assay revealed similar to 15% binding with estrogen receptor. Evaluation of ligand on ER(+) cell line (MCF-7) suggested enhanced and ER-mediated uptake. In vivo assays displayed early tracer accumulation in MCF-7 xenografts with tumor to muscle ratio similar to 6 in 2 h and negligible uptakes in nontargeted organs. MTT assay performed on ER(+) and ER(-) cell lines displayed selective inhibition of ER(+) cancer cell growth with IC50 = 14.3 mu M which was comparable to tamoxifen. The anticancer activity of the ligand is possibly due to the increase in ER beta and suppression of ER alpha protein levels in gene transcription. The studies reveal the potential of (EST)(2)DT as diagnostic imaging agent with the additional benefits in therapy.