title: PET of follicle-stimulating hormone receptor: broad applicability to cancer imaging.
abstract: Selective overexpression of follicle-stimulating hormone receptor (FSHR) inside the vascular endothelium of tumors has been confirmed to play critical roles in angiogenesis, tumor invasion, and metastases. The expression level of FSHR correlates strongly with the response of tumors to antiangiogenic therapies. In this study, an immunoPET tracer was developed for imaging of FSHR in different cancer types. A monoclonal antibody (FSHR-mAb) against FSHR was conjugated with S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) and used for subsequent (64)Cu-labeling. NOTA-FSHR-mAb preserved FSHR specificity/affinity, confirmed by flow cytometry measurements. (64)Cu-labeling was successfully conducted with decent yields (∼25%) and high specific activity (0.93 GBq/mg). The uptake of (64)Cu-NOTA-FSHR-mAb was 3.6 ± 0.8, 13.2 ± 0.7, and 14.6 ± 0.4 %ID/g in FSHR-positive CAOV-3 tumors at 4, 24, and 48 h postinjection, respectively (n = 3), significantly higher (p < 0.05) than that in FSHR-negative SKOV-3 tumors (2.3 ± 1.2, 8.0 ± 0.9, and 9.1 ± 1.3 %ID/g at 4, 24, and 48 h postinjection, respectively (n = 3)) except at 4 h p.i. FSHR-relevant uptake of (64)Cu-NOTA-FSHR-mAb was also readily observed in other tumor types (e.g., triple-negative breast tumor MDA-MB-231 or prostate tumor PC-3). Histology studies showed universal FSHR expression in microvasculature of these four tumor types and also prominent expression in tumor cells of CAOV-3, PC-3, and MDA-MB-231. Correlations between tumor FSHR level and uptake of (64)Cu-NOTA-FSHR-mAb were witnessed in this study. FSHR-specific uptake of (64)Cu-NOTA-FSHR mAb in different tumors enables its applicability for future cancer theranostic applications and simultaneously establishes FSHR as a promising clinical target for cancer.
authors.affiliation: Department of Radiology, ‡Department of Medical Physics, §Materials Science Program, and ∥Department of Biomedical Engineering, University of Wisconsin-Madison , Madison, Wisconsin 53705-2275, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Yan
authors.forename: Sixiang
authors.initials: S
authors.lastname: Shi
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Graves
authors.forename: Lazura K
authors.initials: LK
authors.lastname: Krasteva
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Nickles
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Weibo
authors.initials: W
authors.lastname: Cai
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000175:diagnosis; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes; D003952:Diagnostic Imaging / Q000379:methods*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000175:diagnosis; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000175:diagnosis; D011962:Receptors, FSH / Q000378:metabolism*
chemical_list: D003301:Copper Radioisotopes; D011962:Receptors, FSH
keywords: Cu-64; angiogenesis; follicle-stimulating hormone receptor (FSHR); immunoPET; molecular imaging; positron emission tomography (PET)