title: Characterization of estrogen-receptor-targeted contrast agents in solution, breast cancer cells, and tumors in vivo.
abstract: The estrogen receptor (ER) is a major prognostic biomarker of breast cancer, currently determined in surgical specimens by immunohistochemistry. Two new ER-targeted probes, pyridine-tetra-acetate-Gd chelate (PTA-Gd) conjugated either to 17β-estradiol (EPTA-Gd) or to tamoxifen (TPTA-Gd), were explored as contrast agents for molecular imaging of ER. In solution, both probes exhibited a micromolar ER binding affinity, fast water exchange rate (∼10(7) s(-1)), and water proton-relaxivity of 4.7-6.8 mM(-1) s(-1). In human breast cancer cells, both probes acted as estrogen agonists and enhanced the water protons T1 relaxation rate and relaxivity in ER-positive as compared to ER-negative cells, with EPTA-Gd showing a higher ER-specific relaxivity than TPTA-Gd. In studies of breast cancer tumors in vivo, EPTA-Gd induced the highest enhancement in ER-positive tumors as compared to ER-negative tumors and muscle tissue, enabling in vivo detection of ER. TPTA-Gd demonstrated the highest enhancement in muscle tissue indicating nonspecific interaction of this agent with muscle components. The extracellular contrast agents, PTA-Gd and GdDTPA, showed no difference in the perfusion capacity of ER-positive and -negative tumors confirming the specific interaction of EPTA-Gd with ER. These findings lay a basis for the molecular imaging of the ER using EPTA-Gd as a template for further developments.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Pais
authors.forename: Inbal Eti
authors.initials: IE
authors.lastname: Biton
authors.forename: Raanan
authors.initials: R
authors.lastname: Margalit
authors.forename: Hadassa
authors.initials: H
authors.lastname: Degani
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry; D004967:Estrogens / Q000737:chemistry / Q000493:pharmacokinetics*; D005682:Gadolinium / Q000737:chemistry / Q000493:pharmacokinetics*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013629:Tamoxifen / Q000493:pharmacokinetics*
chemical_list: D003287:Contrast Media; D004967:Estrogens; D011960:Receptors, Estrogen; D013629:Tamoxifen; D005682:Gadolinium