title: Folate receptor-targeted multimodality imaging of ovarian cancer in a novel syngeneic mouse model.
abstract: A new transplantable ovarian tumor model is presented using a novel folate receptor (FR) positive, murine ovarian cancer cell line that emulates the human disease and induces widespread intraperitoneal (i.p.) tumors in immunocompetent mice within 4-8 weeks of implantation. Tumor development was monitored using a new positron emission tomography (PET) FR-targeting reporter with PET/computerized tomography (PET/CT) and fluorescence molecular tomography (FMT) using a commercial FR-targeting reporter. Conventional structural magnetic resonance imaging (MRI) was also performed. Adult female C57BL/6 mice were injected i.p. with 6 × 10(6) MKP-L FR+ cells. Imaging was performed weekly beginning 2 weeks after tumor induction. The albumin-binding, FR-targeting ligand cm09 was radiolabeled with the positron emitter (68)Ga and used to image the tumors with a small animal PET/CT. The FR-reporter FolateRSense 680 (PerkinElmer) was used for FMT and flow cytometry. Preclinical MRI (7 T) without FR-targeting was compared with the PET and FMT molecular imaging. Tumors were visible by all three imaging modalities. PET/CT had the highest imaging sensitivity at 3-3.5 h postadministration (mean %IA/g mean > 6) and visualized tumors earlier than the other two modalities with lower kidney uptake (mean %IA/g mean < 17) than previously reported FR-targeting agents in late stage disease. FMT showed relatively low FR-targeted agent in the bladder and kidneys, but yielded the lowest anatomical image resolution. MRI produced the highest resolution images, but it was difficult to distinguish tumors from abdominal organs during early progression since a FR-targeting MRI reporter was not used. Nevertheless, there was good correlation of imaging biomarkers between the three modalities. Tumors in the mouse ovarian cancer model could be detected using FR-targeted imaging as early as 2 weeks post i.p. injection of tumor cells. An imaging protocol should combine one or more of the modalities, e.g., PET/CT or PET/MRI for optimal tumor detection and delineation from surrounding tissues.
authors.affiliation: Department of Radiology, ‡Cancer Institute, §Department of Obstetrics, Gynecology & Reproductive Sciences, ∥Magee Womens Research Institute, ⊥Department of Pharmacology & Chemical Biology, #Department of Bioengineering, University of Pittsburgh , Pittsburgh, Pennsylvania 15213, United States.
authors.forename: Meltem
authors.initials: M
authors.lastname: Ocak
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Gillman
authors.forename: Jamee
authors.initials: J
authors.lastname: Bresee
authors.forename: Lixin
authors.initials: L
authors.lastname: Zhang
authors.forename: Anda M
authors.initials: AM
authors.lastname: Vlad
authors.forename: Cristina
authors.initials: C
authors.lastname: Müller
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: W Barry
authors.initials: WB
authors.lastname: Edwards
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Anderson
authors.forename: H Michael
authors.initials: HM
authors.lastname: Gach
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D051379:Mice; D064847:Multimodal Imaging / Q000379:methods*; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000000981:diagnostic imaging; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed
chemical_list: D058973:Folate Receptors, GPI-Anchored
keywords: 68Ga; FolateRSense; MRI; PET/CT; cm09; fluorescence molecular tomography; folate receptor targeting; immunocompetent ovarian cancer mouse model