Targeted Microbubbles for Noninvasive Measurement of Tumor VEGF Levels

用于无创测量肿瘤 VEGF 水平的靶向微泡

• 批准号: 8702492
• 负责人: Mark Andrew Borden
• 金额: $ 18.41万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702492
• 关键词: Acoustics; Affect; Affinity; Agar; Back; Binding; Biochemical; Biochemistry; Biological Markers; Biopsy; Blood; Blood Circulation; Blood Vessels; Breast; Breast Cancer Cell; Breast Cancer Model; Cancer Detection; Cancer cell line; Cells; Chemicals; Clinic; Clinical; Clinical Oncology; Complex; Contracts; Contrast Media; Crosslinker; DNA; DNA Sequence; Data; Deep Vein Thrombosis; Detection; Diagnostic Neoplasm Staging; Disease; Drug Formulations; Early Diagnosis; Ensure; Environment; Enzyme-Linked Immunosorbent Assay; Evaluation; Excision; Exhibits; Future; Goals; Health Care Costs; Histology; Image; Imaging Techniques; Implant; In Vitro; Leadership; Lesion; Ligands; Link; MCF10A cells; MCF7 cell; MDA MB 231; Malignant Neoplasms; Mammary Neoplasms; Measurement; Measures; Methodology; Methods; Microbubbles; Modeling; Monitor; Mus; Operating Rooms; Ovarian; Painless; Pancreas; Patients; Procedures; Prognostic Marker; Proteins; Protocols documentation; Recruitment Activity; Reporting; Research; Sampling; Screening for cancer; Signal Transduction; Site; Specificity; Stimulus; Surface; Techniques; Technology; Thrombin; Translating; Ultrasonography; Validation; Vascular Endothelial Growth Factors; Xenograft Model; Xenograft procedure; aptamer; base; cancer imaging; cancer therapy; cancer type; cost; crosslink; design; empowered; experience; feeding; flexibility; improved; in vivo; malignant breast neoplasm; matrigel; outcome forecast; overexpression; pressure; prevent; psychologic; public health relevance; receptor; research study; satisfaction; screening; tool; tumor; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): The aim of the proposed research is to design contrast agents that can measure local levels of soluble Vascular Endothelial Growth Factor (VEGF) via safe, noninvasive means. VEGF helps to form new blood vessels that feed a growing tumor, and thus elevated VEGF levels in the tumor environment correlates negatively with survival in breast and other cancers. Patients who have received a positive result from a cancer screening usually undergo an invasive biopsy to measure the levels of such biomarkers. However, high false positive rates in screening have led to unnecessary biopsies that burden a patient with physical, financial, and psychological costs. Thus it would be ideal to measure biomarker levels in a specific environment - where a specific biomarker may be secreted, overexpressed, or recruited by receptor ligands - through a highly sensitive and specific noninvasive technique. The PIs plan to create such a technique by leveraging their design of stimulus-responsive ultrasound contrasts agents with their experience in using ultrasound for contrast-enhanced cancer imaging. Microbubbles are potent ultrasound contrast agents because ultrasound causes the bubble to expand and contract, generating a nonlinear echo that can be detected with excellent specificity. Biomarker-sensitive activity will be imparted to the VEGF-sensitive microbubbles through placement of aptamers, or DNA sequences with affinity for proteins, around the bubble to form a network of links that prevent the microbubbles from fluctuating in size. VEGF will cause removal of the aptamer strands, restoring shell flexibility an full contrast activity. In previous research, the PI team successfully employed a similar strategy to create microbubbles that exhibited sensitivity to elevated thrombin levels for detection of deep venous thrombosis. In addition, tumor-specific targeting ligands will be added to hold microbubbles at the tumor site, ensuring sufficient signal. Second, the microbubbles will be dually imaged such that comparison of these received signals will provide a more accurate, quantitative measurement of VEGF. Completion of the proposed research will be accomplished through satisfaction of the following specific aims: (1) microbubbles with sensitivity to VEGF will be designed and validated in nonbiological phantoms, (2) new imaging techniques will be designed for microbubble-based quantification of VEGF levels through establishment of signal-pressure relationships, and (3) VEGF will be quantified in breast cancer cell lines in vitro and an in vivo breast cancer xenograft model. The long-term goal is to apply this technology to other types of cancers, including ovarian and pancreatic, and advance these tools for use in clinical oncology.

描述（由申请人提供）：拟议研究的目的是设计能够通过安全、非侵入性方式测量可溶性血管内皮生长因子（VEGF）局部水平的造影剂。 VEGF 有助于形成新血管，为生长中的肿瘤提供营养，因此肿瘤环境中 VEGF 水平升高与乳腺癌和其他癌症的生存呈负相关。从癌症筛查中获得阳性结果的患者通常会进行侵入性活检以测量此类生物标志物的水平。然而，筛查中的高假阳性率导致不必要的活检，给患者带来身体、经济和心理成本的负担。因此，通过高度灵敏和特异性的非侵入性技术测量特定环境中的生物标志物水平是理想的，其中特定的生物标志物可能被受体配体分泌、过度表达或募集。 PI 计划利用他们的刺激响应超声造影剂设计以及使用超声进行对比增强癌症成像的经验来创建这样一种技术。微泡是有效的超声造影剂，因为超声导致气泡膨胀和收缩，产生非线性回波，可以以极好的特异性检测到。通过在气泡周围放置适体或对蛋白质具有亲和力的 DNA 序列，将生物标志物敏感活性赋予 VEGF 敏感微泡，形成连接网络，防止微泡尺寸波动。 VEGF 将导致适体链的去除，恢复壳的灵活性和完整的对比活性。在之前的研究中，PI 团队成功地采用了类似的策略来创建微泡，该微泡对凝血酶水平升高表现出敏感性，用于检测深部 静脉血栓形成。此外，还将添加肿瘤特异性靶向配体，将微泡固定在肿瘤部位，确保足够的信号。其次，微泡将被双重成像，这样接收到的信号的比较将提供 VEGF 的更准确、定量的测量。通过满足以下具体目标来完成拟议的研究：（1）对 VEGF 敏感的微泡将 在非生物体模中进行设计和验证，（2）将设计新的成像技术，通过建立信号-压力关系，基于微泡对 VEGF 水平进行定量，（3）将在体外对乳腺癌细胞系中的 VEGF 进行定量，并通过 体内乳腺癌异种移植模型。长期目标是将这项技术应用于其他类型的癌症，包括卵巢癌和胰腺癌，并推进这些工具在临床肿瘤学中的应用。