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

微泡是封装的气体颗粒，其响应于压力而压缩和膨胀其形状。 并产生超过常规超声反向散射强声学信号。 尺寸范围从2到6微米，微泡在血流中持续几分钟， 评估它们在组织微血管水平的存在。微泡已经找到了进入 作为超声造影剂的临床应用-例如用于肝脏病变成像或超声心动图。 对这一建议很重要的是发现微泡可以靶向表面上的特定抗原 通过将配体附着在微泡壳上来分离血管内皮细胞。微泡功能化， 在分子水平上提供关于脉管系统的详细信息。 血管生成，即新血管的募集，发生在卵巢癌的非常早期阶段 VEGFA/EGFR 2轴的发育和激活在此过程中起着至关重要的作用。我们的初步 数据表明，VEGFR 2在卵巢癌的肿瘤血管中上调， 在降低风险的输卵管卵巢切除术时发现的癌症。在小动物肿瘤模型中， 使用对比增强超声（CEUS）进行经验证的非侵入性肿瘤血管生成成像， VEGFR 2和/或OvPs靶向的微泡，并证明这些微泡具有高的 在细胞培养物和活小鼠中分别对VEGFR 2-和OvPs-表达细胞的结合特异性。我们 还表明，超声信号放大是可能的，使用双靶向微泡。 在本提案的目标1中，我们将通过开展以下活动将我们的发现从小动物模型转化为临床： 第一个VEGFR 2靶向微泡CEUS成像卵巢癌的1期临床试验 血管网由于血管内皮细胞的分子表型因组织部位而异， 激活状态选择最佳靶向抗原是优化该方法的关键步骤。在目标2中 我们将鉴定和验证新的内皮细胞表面蛋白，这些蛋白可能是比 与VEGR 2互补，并验证这些标记物作为小鼠体内血管生成成像靶点 模型 相关性（见说明）： 该提案的主要目的是验证和完善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。的 这种方法有可能通过早期发现改善所有卵巢癌妇女的预后 选择和监测卵巢癌对抗血管生成药物的反应 疗法

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.