Multimodal Imaging and Therapy of Ovarian Cancer

ABSTRACT Ovarian cancer is the deadliest gynecological malignancy. Nearly 75% of patients present with metastatic intra- peritoneal (i.p.) disease. Radiation, chemotherapy, and immunotherapy are not very effective. In comparison, the degree of cytoreduction at surgery is one of the most important factors for prognosis and methods to improve its efficacy are sorely needed. Detection pre-surgically and at surgery are major constraints. Presently, pre- surgical imaging is limited in detecting i.p. disease, and, surgery is limited because it relies on the naked eye to identify nodules for resection. Moreover, some nodules are in eloquent locations that preclude surgery. A theranostic agent that upon a single injection enables in vivo imaging of i.p. disease for pre-surgical planning, near-infrared (NIR) imaging to visualize tumors at surgery for resection, and photodestruction of tumors in eloquent locations is a key clinical need in ovarian cancer. For MR imaging, we created dual-Gd liposomal nanoparticles, with two gadolinium (Gd) presentations upon the liposome to increase relaxivity, and demonstrated that they have ~10,000 times greater relaxivity/nanoparticle than current commercially available MR contrast agents. Dual-Gd is based on FDA approved building blocks. For NIR imaging, we incorporated indocyanine green (ICG), the only FDA approved NIR fluorophore. We found that unlike similarly dosed ICG or clinically available Gd-chelates, our new dual-mode dual-Gd (DM-Dual-Gd) nanoparticle detects i.p. tumors by both MR and NIR in two different human ovarian cancer models two days after a single systemic injection. The long tumor residence time should enable non-invasive imaging, presurgical planning, and surgery. Moreover, ICG can enable photodestruction. To enhance, tumor localization for imaging and treatment, we propose to decorate the particles for proven/novel targets for ovarian cancer. To improve visualization at surgery, we will capitalize on the second NIR window that is less prone to photon absorption and scattering by tissues. In the appropriate context, ICG can fluoresce in this window and can be excited with appropriate light wavelengths to produce heat and oxygen radicals. We plan to exploit the latter for photodestruction of ovarian tumors. For practical needs of clinical translation, we propose to test the accuracy of these methods for detecting ovarian tumor implants and hypothesize that pre-surgical MR imaging and surgical optical imaging/photodestruction employing DM-Dual-Gd-based nanoparticles can improve overall survival. Thus, this proposal seeks to create a new paradigm for approaching ovarian cancer that enables presurgical planning, surgical resection, and tumor photodestruction after a single nanoparticle injection. We will test the hypotheses that SA1: ovarian tumor delivery can be augmented by targeting DM-Dual-Gd to proven or novel imaging targets; SA2: ovarian tumor detection can be improved using the NIR II window compared to the NIR I window; SA3: DM-Dual-Gd-based nanoparticles enable photodestruction of ovarian tumors; SA4: pre-surgical MR imaging and surgical NIR imaging employing DM-Dual-Gd can improve survival of models of i.p. ovarian cancer.