title: Bivalent Approach for Homodimeric Estradiol Based Ligand: Synthesis and Evaluation for Targeted Theranosis of ER(+) Breast Carcinomas.
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.
authors.affiliation: Institute of Nuclear Medicine & Allied Sciences, DRDO , Brig. SK Mazumdar Marg, Delhi-110054, India.|Department of Chemistry, Indian Institute of Technology , Delhi-110016, India.
authors.forename: Kanchan
authors.initials: K
authors.lastname: Chauhan
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute , Lucknow-226031, India.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Arun
authors.affiliation: Institute of Nuclear Medicine & Allied Sciences, DRDO , Brig. SK Mazumdar Marg, Delhi-110054, India.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Singh
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute , Lucknow-226031, India.
authors.forename: Murli
authors.initials: M
authors.lastname: Manohar
authors.affiliation: Institute of Nuclear Medicine & Allied Sciences, DRDO , Brig. SK Mazumdar Marg, Delhi-110054, India.
authors.forename: Krishna
authors.initials: K
authors.lastname: Chuttani
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute , Lucknow-226031, India.
authors.forename: Rituraj
authors.initials: R
authors.lastname: Konwar
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute , Lucknow-226031, India.
authors.forename: Anila
authors.initials: A
authors.lastname: Dwivedi
authors.affiliation: Institute of Nuclear Medicine & Allied Sciences, DRDO , Brig. SK Mazumdar Marg, Delhi-110054, India.
authors.forename: Ravi
authors.initials: R
authors.lastname: Soni
authors.affiliation: Department of Chemistry, Indian Institute of Technology , Delhi-110016, India.
authors.forename: Ajai Kumar
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Institute of Nuclear Medicine & Allied Sciences, DRDO , Brig. SK Mazumdar Marg, Delhi-110054, India.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mishra
authors.affiliation: Institute of Nuclear Medicine & Allied Sciences, DRDO , Brig. SK Mazumdar Marg, Delhi-110054, India.
authors.forename: Anupama
authors.initials: A
authors.lastname: Datta
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D019281:Dimerization; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D006801:Humans; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D011960:Receptors, Estrogen / Q000378:metabolism*; D000068936:Theranostic Nanomedicine; D014018:Tissue Distribution
chemical_list: D008024:Ligands; D011960:Receptors, Estrogen; D004958:Estradiol