Multimodal Imaging and Therapy of Ovarian Cancer

摘要 卵巢癌是最致命的妇科恶性肿瘤。近75%的患者存在转移性内- 腹膜（i. p.）疾病放疗、化疗和免疫疗法都不是很有效。相比之下， 手术中细胞减少的程度是预后和改善方法的最重要因素之一。 它效力是迫切需要的。手术前和手术中的检测是主要的限制。目前，预- 手术成像在检测腹膜内疾病方面是有限的，并且手术也是有限的，因为它依赖于肉眼， 识别结节以便切除。此外，一些结节位于无法手术的有利位置。一 在单次注射时能够对腹膜内疾病进行体内成像以用于手术前计划的治疗诊断剂， 近红外（NIR）成像，在手术切除时可视化肿瘤， 在卵巢癌中，重要的临床需要是明确的位置。对于MR成像，我们创建了双Gd脂质体 纳米颗粒，在脂质体上具有两个钆（Gd）呈现以增加弛豫性，以及 证明它们具有比目前市售的约10，000倍的弛豫率/纳米颗粒 MR造影剂。Dual-Gd基于FDA批准的构建块。对于NIR成像，我们将 吲哚菁绿色（ICG），唯一FDA批准的NIR荧光团。我们发现，与剂量相似的ICG或 临床上可用的Gd螯合物，我们的新的双模式双Gd（DM-Dual-Gd）纳米颗粒通过以下方式检测腹膜内肿瘤： 在单次全身注射后两天，在两种不同的人卵巢癌模型中进行MR和NIR。的 长的肿瘤停留时间应该能够实现非侵入性成像、术前计划和手术。此外，委员会认为， ICG可以实现光破坏。为了增强肿瘤的成像和治疗定位，我们建议 修饰颗粒以用于卵巢癌的经证实的/新的靶点。为了提高手术的可视性，我们将 利用第二NIR窗口，其不易于被组织吸收和散射光子。在 在适当的情况下，ICG可以在该窗口中发荧光，并且可以用适当的光波长激发， 产生热和氧自由基。我们计划利用后者对卵巢肿瘤进行光破坏。为 根据临床翻译的实际需要，我们建议测试这些方法检测卵巢癌的准确性 并假设术前MR成像和手术光学成像/光破坏 使用基于DM-Dual-Gd的纳米颗粒可以改善总体存活率。因此，这项建议旨在建立一个 卵巢癌治疗的新模式，使术前计划，手术切除和肿瘤 在单次纳米颗粒注射后的光破坏。我们将检验SA 1：卵巢肿瘤 通过将DM-Dual-Gd靶向到已证实的或新的成像靶点，可以增强递送; SA 2：卵巢肿瘤 与NIR I窗口相比，使用NIR II窗口可以改善检测; SA 3：基于DM-双Gd 纳米颗粒能够光破坏卵巢肿瘤; SA 4：术前MR成像和手术NIR 采用DM-Dual-Gd的成像可以改善腹膜内卵巢癌模型的存活率。

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.