Development of a Novel Targeted Ultrasound Microbubble for Early Detection of Ovarian Cancer
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Date
2020-02
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Abstract
Ovarian cancer is the deadliest gynecologic malignancy, with an overall 5-year survival rate of 47%. Although ovarian cancer has 5-year survival of 70-80% in patients diagnosed during early-stage disease, most patients are not diagnosed until late-stage. Transvaginal ultrasound, the imaging gold standard for routine examination of ovarian masses, is limited in its ability to distinguish between benign and malignant masses. This deficiency can be improved via targeted ultrasound, a novel modality involving molecularly targeted, micron-sized gas-filled bubbles that directed against markers expressed on the endothelial surface of blood vessels. Tissue factor (TF) is a unique, tumor-specific marker expressed in ovarian cancer. TF is also associated with angiogenesis - an early event in ovarian tumor growth and progression. The hypothesis of this study is that ovarian cancer can be detected in early-stage disease using TF-targeted ultrasound microbubbles. Immunohistochemistry (IHC) was performed to examine TF expression on both murine and patient-derived ovarian tumor tissues, as well as on tumor-associated vascular endothelial cells (VECs). Conjugation of anti-TF to fluorescent polystyrene microbeads, which served as microbubble surrogates for initial proof of concept, and microbubbles was achieved through streptavidin-biotin bridging chemistry. In vitro binding assays were performed to assess the binding efficacy of these microbeads and microbubbles. Results of this study demonstrated TF expression on ovarian tumor-associated VECs, in both murine and patient tumor tissues. Additionally, TF-targeted microbeads and microbubbles were shown to successfully bind to TF-expressing ovarian cancer cells. TF-targeted microbubbles were also shown to bind to VEGF-stimulated endothelial cells which served as an in vitro model of angiogenic endothelium. Successful development of a novel targeted ultrasound microbubble directed against a unique, tumor-specific marker, such as TF, could have significant implications towards increasing the number of early-stage ovarian cancer diagnoses. This work shows promise to be easily translated for clinical use, which would thereby have a positive impact by decreasing the morbidity and mortality associated with ovarian cancer.
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Health Sciences: 1st Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
Keywords
Targeted Ultrasound, Ovarian Cancer, Pathology, Tissue Factor, Angiogenesis