Targeted Microbubble Contrast-Enhanced Ultrasound Imaging of the Ovarian Cancer V

微泡是一种被封装的气体颗粒，它可以压缩和扩张它们的形状，以响应 电离源，并产生超过常规超声背向散射的强声信号。 大小从2微米到6微米不等，微泡在血液中持续几分钟，使 在组织微血管水平上评估它们的存在。微泡已经找到了进入 作为超声造影剂的临床应用-例如，肝脏病变的成像或超声心动图。 这项提议的重要发现是微泡可以针对表面的特定抗原。 通过将配体连接到微泡外壳来识别血管内皮细胞。Microbbuble在此实现了功能化 方法在分子水平上提供了关于血管系统的详细信息。 血管生成，即新血管的募集，发生在卵巢癌的早期阶段。 VEGFA/EGFR2轴的发育和激活在这一过程中起着至关重要的作用。我们的预赛 数据显示，VEGFR2在卵巢癌的肿瘤血管中上调，包括隐匿性的 在降低风险的输卵管卵巢切除术时发现癌症。在小动物肿瘤模型中 使用对比增强超声(CEUS)验证非侵入性肿瘤血管生成成像 VEGFR2和/或OVP靶向微泡，并证明这些微泡具有高 在细胞培养和活着的小鼠中，分别与表达VEGFR2和OVPs的细胞结合的特异性。我们 还表明利用双靶向微泡可以放大超声信号。 在这项提案的目标1中，我们将通过以下方式将我们的发现从小动物模型转化到临床 首次应用VEGFR2靶向微泡超声显影卵巢癌的1期临床试验 血管网络。因为血管内皮细胞的分子表型因组织部位和 激活状态选择用于靶向的最佳抗原是优化方法的关键步骤。在AIM 2 我们将识别和验证新的内皮细胞表面蛋白，这些蛋白可能是比或 与VEGR2互补并验证其作为小鼠体内血管生成成像靶点的有效性 模特们。 相关性(请参阅说明)： 这项提议的主要目标是验证和提炼分子靶向微泡造影剂 增强超声(CEUS)用于卵巢癌血管网络的非侵入性体内成像。这个 这种方法有可能通过早期发现来改善所有卵巢癌患者的预后 和疾病的诊断以及卵巢癌对抗血管生成药物的选择和监测 心理治疗。

Microbubbles are encapsulated gaseous particles that compress and expand their shape in response to an insonation source and generate strong acoustic signals that exceed conventional ultrasound backscatter. Ranging in size from 2 to 6 um, microbubbles persist in the blood stream for several minutes enabling assessment of their presence at the tissue microvascular level. Microbubbles have found their way into clinical application as ultrasound contrast agents - e.g. for imaging of liver lesions or echocardiography. Important to this proposal is the finding that microbubbles can be targeted to specific antigens on the surface of vascular endothelial cells by attaching ligands to the microbubble shell. Microbbubles functionalized in this way provide detailed information on the vasculature at a molecular level. Angiogenesis, the recruitment of new blood vessels, occurs at a very early stage in ovarian cancer development and activation ofthe VEGFA/EGFR2 axis plays a crucial role in the process. Our preliminary data demonstrates that VEGFR2 is up-regulated in tumor vessels from ovarian cancer including occult cancer identified at the time of risk-reduction salpingo-oophorectomy. In small animal tumor models we validated non-invasive tumor angiogenesis imaging using contrast enhanced ultrasound (CEUS) with VEGFR2- and/or OvPs-targeted microbubbles and demonstrated that these microbubbles have a high specificity for binding to VEGFR2- and OvPs-expressing cells, respectively, in cell culture and living mice. We also show that ultrasound signal amplification is possible using dual-targeted microbubbles. In Aim 1 of this proposal we will translate our findings from small animal models to the clinic by conducting the first ever Phase 1 clinical trial of VEGFR2 targeted microbubble CEUS to image the ovarian cancer vascular network. Because the molecular phenotype of vascular endothelial cells varies by tissue site and activation state selecting the best antigens for targeting is a critical step in optimizing the approach. In Aim 2 we wilt identify and validate novel endothelial cell surface proteins that may be better markers than or complementary to VEGR2 and validate these markers as in-vivo angiogenesis imaging targets in mouse models. RELEVANCE (See Instructions): The primary objective of this proposal is to validate and refine molecularly targeted microbubble contrast enhanced ultrasound (CEUS) for non-invasive, in-vivo imaging ofthe ovarian cancer vascular network. The approach has the potential to improve outcomes for all women with ovarian cancer through early detection and diagnosis ofthe disease and selecting and monitoring the response of ovarian cancer to anti-angiogenic therapy.