Multimodal Imaging and Therapy of Ovarian Cancer

卵巢癌的多模态成像和治疗

• 批准号: 10472664
• 负责人: VIKAS KUNDRA
• 金额: $ 50.56万
• 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 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472664
• 关键词: Abdomen; Animal Model; Cancer Model; Chelating Agents; Clinical; Combined Modality Therapy; Contrast Media; Data; Detection; Diagnosis; Dimensions; Disease; Dose; Excision; Eye; FDA approved; Gadolinium; Goals; Human; Image; Image-Guided Surgery; Immunotherapy; Implant; In Vitro; Indocyanine Green; Injections; Integrin alphaVbeta3; Lesion; Light; Liposomes; Location; Magnetic Resonance Imaging; Malignant Female Reproductive System Neoplasm; Malignant neoplasm of ovary; Methods; Modeling; Multimodal Imaging; Near-infrared optical imaging; Nodule; Operative Surgical Procedures; Ovarian; PUVA Photochemotherapy; Patients; Peritoneal Diseases; Permeability; Photons; Prognosis; Publishing; Radiation; Radiation therapy; Reactive Oxygen Species; Resolution; Sensitivity and Specificity; Shapes; Signal Transduction; Staging; Technology; Testing; Time; Tissues; Visualization; Woman; absorption; base; chemotherapy; clinical translation; fluorophore; folate-binding protein; improved; in vivo imaging; intraperitoneal; nanoparticle; nanoscale; non-invasive imaging; novel; optical imaging; ovarian neoplasm; particle; phantom model; photothermal therapy; residence; survival prediction; targeted imaging; theranostics; tumor

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.

摘要 卵巢癌是最致命的妇科恶性肿瘤。近75%的转移性血管内转移患者 腹膜(Ip)疾病。放射治疗、化疗和免疫治疗都不是很有效。相比之下， 手术中细胞减少的程度是影响预后的重要因素之一，也是改善预后的方法之一。 它的效力是迫切需要的。手术前和手术时的检测是主要的制约因素。目前，Pre- 外科成像在检测I.P.方面有限。疾病，手术是有限的，因为它依赖于肉眼 确定要切除的结节。此外，一些结节位于有说服力的位置，无法进行手术。一个 一次注射即可在体内对I.P.进行成像的消毒剂。用于手术前计划的疾病， 近红外(NIR)成像用于在手术切除时可视化肿瘤，并对肿瘤进行光破坏 口才好的位置是卵巢癌的关键临床需求。对于磁共振成像，我们创建了双Gd脂质体 纳米颗粒，在脂质体上加入两种Gd(Gd)以增加松弛能力，以及 证明了它们具有比目前商业上可获得的松弛系数/纳米粒子大约10,000倍 磁共振造影剂。Dual-Gd基于FDA批准的构建块。对于近红外成像，我们加入了 吲哚青绿(ICG)，FDA唯一批准的近红外荧光团。我们发现，与类似剂量的ICG或 临床上可用的Gd-螯合物，我们新的双模式双Gd(DM-Dual-Gd)纳米颗粒可以检测I.P.肿瘤来源： 在单次全身注射两天后，两种不同的人卵巢癌模型中的MR和NIR。这个 较长的肿瘤滞留时间应使非侵入性成像、术前计划和手术成为可能。此外， ICG可以实现光破坏。为了加强肿瘤的定位，以便成像和治疗，我们建议 修饰颗粒，使其成为治疗卵巢癌的有效/新颖靶点。为了改善手术中的视觉效果，我们将 利用第二个近红外窗口，它不太容易被组织吸收和散射。在 在适当的情况下，ICG可以在该窗口中荧光，并可以用适当的光波长来激发以 产生热量和氧自由基。我们计划利用后者进行卵巢肿瘤的光破坏。为 临床翻译的实际需要，我们建议测试这些方法检测卵巢的准确性 肿瘤植入和假设手术前磁共振成像和手术光学成像/光破坏 使用基于Dm-Dual-Gd的纳米颗粒可以提高总体存活率。因此，这项提案寻求创建一个 处理卵巢癌的新范例，使术前计划、手术切除和肿瘤成为可能 一次纳米粒子注射后的光破坏。我们将检验SA1：卵巢肿瘤的假设 可以通过将DM-Dual-Gd靶向已证实的或新的成像靶点来扩大递送；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：DM-基于Dual-Gd 纳米颗粒能够对卵巢肿瘤进行光破坏；SA4：手术前磁共振成像和手术近红外 应用DM-Dual-Gd进行显像可提高I.P.模型的存活率。卵巢癌。