Multimodal Imaging and Therapy of Ovarian Cancer

卵巢癌的多模态成像和治疗

• 批准号: 10573582
• 负责人: VIKAS KUNDRA
• 金额: $ 52.97万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573582
• 关键词: Multimodal; Imaging; Therapy; 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.

抽象的 卵巢癌是最致命的妇科恶性肿瘤。近75％的患者患有转移性的患者 腹膜（i.p.）疾病。放射，化学疗法和免疫疗法不是很有效。相比之下， 手术中的细胞减少程度是预后和改善方法的最重要因素之一 迫切需要它的功效。术前和手术中的检测是主要限制。目前， 手术成像在检测I.P.时受到限制。疾病，并且手术受到限制，因为它依赖于肉眼 确定切除结节。此外，在雄辩的位置，一些结节排除了手术。一个 单一注射后，可以实现i.p.的体内成像。术前计划的疾病， 近红外（NIR）成像以可视化手术时的肿瘤以切除，并在 雄辩的地方是卵巢癌的关键临床需求。对于MR成像，我们创建了双GD脂质体 纳米颗粒，在脂质体上有两个gdolinium（GD），以增加松弛性，并且 证明它们的松弛度/纳米颗粒比市场高约10,000倍 先生对比剂。 Dual-GD基于FDA批准的构件。对于NIR成像，我们合并了 吲哚烷绿色（ICG），唯一批准的NIR荧光团。我们发现，与同样的剂量ICG或 临床上可用的GD螯合物，我们的新型双模式双GD（DM Dual-GD）纳米颗粒检测I.P.肿瘤是 单次全身注射两天后，两种不同的人类卵巢癌模型中的MR和NIR均在两种不同的人类卵巢癌模型中。这 较长的肿瘤停留时间应实现非侵入性成像，术前计划和手术。而且， ICG可以启用光电铸造。为了增强，肿瘤定位用于成像和治疗，我们建议 为卵巢癌的经过验证/新型靶标的颗粒装饰。为了改善手术中的可视化，我们将 在第二个NIR窗口上大写，该窗口不太容易被组织吸收和散射。在 适当的上下文，ICG可以在此窗口中荧光，并且可以通过适当的光波长激发到 产生热量和氧自由基。我们计划利用后者来进行卵巢肿瘤的光死亡。为了 临床翻译的实际需求，我们建议测试这些方法检测卵巢的准确性 肿瘤植入物并假设手术前MR成像和手术光学成像/光电隔离 采用基于DM DM DM DM基于DM的纳米颗粒可以改善总体生存率。因此，该建议旨在创建一个 用于接近卵巢癌的新范式，可实现术前计划，手术切除和肿瘤 一次纳米颗粒注射后的光电毁灭。我们将测试SA1：卵巢肿瘤的假设 可以通过靶向DM-Dual-GD来增强传递，以证明或新颖的成像目标； SA2：卵巢肿瘤 与NIR I窗口相比，使用NIR II窗口可以改进检测； SA3：基于DM DM-Dual-GD 纳米颗粒可以光毁灭卵巢肿瘤； SA4：手术前MR成像和手术NIR 采用DM Dual-GD的成像可以提高腹腔内i.p.的生存率。卵巢癌。