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

Bioconjug Chem. 2016 Apr 20;27(4):961-72. doi: 10.1021/acs.bioconjchem.6b00024. Epub 2016 Mar 29.

Abstract

The synthesis of estradiol based bivalent ligand [(EST)2DT] is reported and its potential for targeted imaging and therapy of ER(+) tumors has been evaluated. For the purpose, ethinylestradiol was functionalized with an azidoethylamine moiety via click chemistry. The resultant derivative was reacted in a bivalent mode with DTPA-dianhydride to form the multicoordinate chelating agent, (EST)2DT which displayed capability to bind (99m)Tc. The radiolabeled complex, (99m)Tc-(EST)2DT was obtained in >99% radiochemical purity and 20-48 GBq/μmol of specific activity. RBA assay revealed ∼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 ∼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 μM which was comparable to tamoxifen. The anticancer activity of the ligand is possibly due to the increase in ERβ and suppression of ERα protein levels in gene transcription. The studies reveal the potential of (EST)2DT as diagnostic imaging agent with the additional benefits in therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / diagnosis*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / therapy*
  • Cell Line, Tumor
  • Dimerization
  • Estradiol / metabolism*
  • Female
  • Humans
  • Ligands
  • Mice
  • Mice, Nude
  • Receptors, Estrogen / metabolism*
  • Theranostic Nanomedicine*
  • Tissue Distribution

Substances

  • Ligands
  • Receptors, Estrogen
  • Estradiol