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.

Multifunctionalized biocatalytic P22 nanoreactor for combinatory treatment of ER+ breast cancer

“…Therefore, an estrogen derivative, 17α-ethynylestradiol (EE2) was chosen as targeting ligand due to its high specificity towards ER+, and its synthetic accessibility. The chemical substitution at the ethynyl position of EE2 is well documented for its retained bioactivity [ 32 , 38 , 39 ]. Thus, chemical modification was performed at the ethynyl position of EE2 for covalent functionalization on particles surface using a heterofunctional PEG as a linker.…”

“…The chemical substitution at the ethynyl position of 17α-ethynylestradiol (EE2) is well documented for its retained bioactivity [ 32 , 38 , 39 ]. Thus, amine functionality at the ethynyl position of EE2 was introduced by Sonogashira coupling with 4-bromoaniline to obtain ESTAm and characterized using NMR, HRMS and FTIR (Additional file 1 : Figures S1–S3).…”

“…Estrogen receptor (ER) belongs to the hormone receptor family and mainly localized on the cell membrane and intracellularly [ 29 , 30 ]. It possesses a very high affinity towards its cognate ligands (estrogens) and thus, estradiol based ligands have been widely used as selective targeting agents for breast cancer imaging and therapy [ 31 , 32 ].…”

One-Step 18F-Labeling of Estradiol Derivative for PET Imaging of Breast Cancer

“…Therefore, development of novel effective early diagnosis methods is critical for the treatment and survival of patients with breast cancer. It is acknowledged that estrogen plays an important role in the initiation and progression of breast cancer [ 2 , 3 ]. The stimulatory effect of estrogen is mediated by nuclear estrogen receptors (ERs) [ 4 ].…”

“…The understanding of ER level is also essential for prognosis and optimization of the treatment strategy. The ER-positive (ER + ) tumors often respond to the hormonal therapy, whereas the ER-negative (ER − ) tumors usually require the surgical and chemotherapeutic interventions [ 2 , 6 , 7 ].…”