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（由申请方提供）：拟定研究的目的是设计造影剂，通过安全、无创的方法测量可溶性血管内皮生长因子（VEGF）的局部水平。VEGF有助于形成为生长中的肿瘤提供营养的新血管，因此肿瘤环境中VEGF水平升高与乳腺癌和其他癌症的存活率呈负相关。从癌症筛查中获得阳性结果的患者通常会接受侵入性活检以测量这些生物标志物的水平。然而，筛查中的高假阳性率导致了不必要的活检，给患者带来了身体、经济和心理上的负担。因此，理想的是通过高度敏感和特异的非侵入性技术测量特定环境中的生物标志物水平-其中特定生物标志物可能被分泌、过表达或被受体配体募集。PI计划通过利用他们的刺激响应超声造影剂的设计以及他们在使用超声进行对比增强癌症成像方面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，可以以优异的特异性检测。通过在气泡周围放置适体或对蛋白质具有亲和力的DNA序列以形成防止微泡大小波动的连接网络，将生物标志物敏感活性赋予VEGF敏感的微泡。VEGF将导致适体链的去除，恢复外壳的灵活性和完全的对比活性。在以前的研究中，PI团队成功地采用了类似的策略来创建微泡，这些微泡对凝血酶水平升高表现出敏感性，用于检测深部血栓。 静脉血栓此外，将添加肿瘤特异性靶向配体以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，使得这些接收到的信号的比较将提供VEGF的更准确的定量测量。通过满足以下具体目标，完成拟议的研究：（1）对VEGF敏感的微泡将 将在非生物模型中设计和验证，（2）将设计新的成像技术，通过建立信号-压力关系，基于微泡定量VEGF水平，和（3）将在体外乳腺癌细胞系中定量VEGF， 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，并推动这些工具在临床肿瘤学中的应用。