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

卵巢癌的靶向微泡超声造影 V

• 批准号: 7727514
• 负责人: CHARLES DRESCHER
• 金额: $ 28.29万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727514
• 关键词: Abdomen; Acoustics; Animal Model; Animals; Antibodies; Antibody Affinity; Antigen Targeting; Antigens; Asia; Benign; Binding; Blood; Blood Vessels; Canada; Cancer Model; Cell Culture Techniques; Cell Surface Proteins; Cells; Clinic; Clinical; Contrast Media; Data; Data Set; Detection; Development; Diagnosis; Diagnostic Imaging; Disease; Dose; Early Diagnosis; Echocardiography; Encapsulated; Endothelial Cells; Enrollment; Europe; Goals; Human; Image; Instruction; Integrins; Lesion; Lesion by Morphology; Life; Ligands; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Microbubbles; Microbubbles Ultrasound Contrast Medium; Modeling; Molecular; Molecular Profiling; Monitor; Mus; Natural regeneration; Normal tissue morphology; Operative Surgical Procedures; Outcome; Ovarian; Ovary; Patients; Pattern; Pelvic Inflammatory Disease; Pelvis; Peptides; Perfusion; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; Physiologic Neovascularization; Play; Postmenopause; Premenopause; Principal Investigator; Process; Proteins; Proteome; Proteomics; Relative (related person); Risk Reduction; Role; Safety; Salpingo-Oophorectomy; Screening for Ovarian Cancer; Serous; Shapes; Signal Transduction; Site; Source; Specificity; Staging; Stream; Streptavidin; Surface; Testing; Time; Tissues; Translating; Translational Research; Tumor Angiogenesis; Ultrasonography; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor-2; Western Blotting; Woman; Work; Xenograft procedure; angiogenesis; anticancer research; cancer diagnosis; cancer surgery; clinical application; corpus luteum; density; genome-wide; immunogenicity; improved; in vivo; liver imaging; molecular phenotype; mouse model; next generation; novel; novel marker; ovarian neoplasm; particle; response; subcutaneous; success; transcriptomics; tumor; volunteer

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.

微泡是封装的气态颗粒，其形状会随着压力的变化而压缩和膨胀。 声源并产生超过传统超声反向散射的强声信号。 微泡的尺寸范围为 2 至 6 微米，可在血流中持续几分钟，从而能够 评估它们在组织微血管水平上的存在。微气泡已经找到了进入 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。 该提案的重要之处在于发现微泡可以靶向表面上的特定抗原 通过将配体附着到微泡壳上来形成血管内皮细胞。微泡在此功能化 方式提供分子水平上脉管系统的详细信息。 血管生成（新血管的募集）发生在卵巢癌的早期阶段 VEGFA/EGFR2轴的发育和激活在此过程中起着至关重要的作用。我们的初步 数据表明 VEGFR2 在卵巢癌（包括隐匿性卵巢癌）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癌症。在小动物肿瘤模型中，我们 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 OvPs 靶向微泡并证明这些微泡具有高 在细胞培养物和活体小鼠中分别特异性结合表达 VEGFR2 和 OvPs 的细胞。我们 还表明使用双目标微泡可以放大超声信号。 在本提案的目标 1 中，我们将通过进行以下研究将我们的发现从小动物模型转化为临床： 有史以来第一个 VEGFR2 靶向微泡 CEUS 对卵巢癌进行成像的 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而异， 激活状态选择最佳抗原进行靶向是优化方法的关键步骤。目标 2 我们将鉴定并验证新的内皮细胞表面蛋白，它们可能是比或更好的标记物 与 VEGR2 互补并验证这些标记物作为小鼠体内血管生成成像靶标 模型。 相关性（参见说明）： 该提案的主要目标是验证和完善分子靶向微泡对比 增强超声 (CEUS) 用于卵巢癌血管网络的非侵入性体内成像。这 该方法有可能通过早期检测改善所有卵巢癌女性的预后 疾病的诊断以及选择和监测卵巢癌对抗血管生成药物的反应 治疗。