Hollow Silica-Polymer Nanocomposites for Stimulus-Responsive Ultrasound Contrast

用于刺激响应超声对比的中空二氧化硅聚合物纳米复合材料

• 批准号: 9108558
• 负责人: Andrew P Goodwin
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-07 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9108558
• 关键词: Acoustics; Adriamycin PFS; Biochemical; Biological Markers; Biopsy; Blood; Breast; Breast Cancer Patient; Breast Cancer cell line; Cancer Detection; Cancer Patient; Cell Culture Techniques; Cell Line; Cells; Chemicals; Cleaved cell; Clinic; Contrast Media; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Disulfides; Drug resistance; Equilibrium; Evaluation; Excision; Future; Gases; Generations; Glutathione; Histology; Image; In Vitro; Lesion; MCF10A cells; MCF7 cell; Malignant Neoplasms; Mammary Neoplasms; Mammography; Methodology; Modeling; Monitor; Neoplasm Metastasis; Oxidation-Reduction; Penetration; Polymers; Procedures; Research; Research Personnel; Resolution; Scheme; Signal Transduction; Silicon Dioxide; Staging; Stimulus; Stream; Thick; Translating; Tumor stage; Ultrasonography; Validation; accurate diagnosis; base; cancer cell; cancer imaging; capsule; contrast enhanced; cost; crosslink; cytotoxicity; design; disulfide bond; experience; flexibility; imaging modality; improved; matrigel; nanocapsule; nanocomposite; nanoscale; nanostructured; outcome forecast; particle; polyacrylamide; prevent; psychologic; public health relevance; research study; response; submicron; technology development; tool; tumor; uptake

 DESCRIPTION (provided by applicant): This proposal describes the synthesis and validation of `smart' ultrasound contrast agents that become active in response to interaction with localized biochemicals for non-invasive, accurate diagnosis and staging of breast tumors. Biopsy and histology are often performed to investigate suspicious lesions found in a routine mammogram because these procedures provide the most relevant information for diagnosis and staging of tumors. However, biopsies are invasive, costly and potentially dangerous. The development of a non-invasive tool that could reliably and inexpensively image tumors would help to reduce the number of unnecessary biopsies for breast cancer patients and the associated physical, financial, and psychological costs. In this proposal, we seek to develop high-resolution ultrasound imaging methods to identify accurately if suspicious lesions in mammograms are worth studying or treating further, as well as screen for potential drug resistance. Ultrasound has been successful for contrast-enhanced blood pool imaging, but the contrast agents often required to improve image resolution are unable to accumulate within the extravascular space owing to their microscale sizes, thus preventing the staging of tumors. Better tumor penetration can be achieved by utilizing sub-micron contrast agents; unfortunately, these cannot provide high contrast due to lower acoustic scattering cross-sections and potential instability. The balance between size and response to ultrasound can be resolved by using responsive contrast agents that become only active after uptaken by the target cancer cells. In such a scheme, the background signal coming from the contrast agents that are still in the blood stream can be eliminated and contrast of the ultrasound images may be improved accordingly. The proposed research describes the design, synthesis, and evaluation of nanoscale ultrasound contrast agents capable of activating only in the presence of intracellular levels of glutathione (GSH) to determine tumor prognosis noninvasively. We will produce disulfide cross-linked polymer and silica based shells that can be digested by the intracellular GSH levels associated with metastatic disease and potentially drug resistance. Reduction of disulfide crosslinks will soften the shells and allow observation of these contrast agents at a lower imaging power, where great nonlinear signal difference between ON and OFF states of contrast agents is expected. PI Goodwin and Co-Investigator Yildirim will combine their expertise to accomplish this research through completion of the following specific aims: 1. Design and validation of redox-responsive single-layer polymer capsules with sensitivity to GSH; 2. Design and validation of redox-responsive double-layered polymer capsules for longer-term monitoring of cells; and 3. Quantification of GSH in breast cancer cell lines in vitro.

 描述（由申请人提供）：该提案描述了“智能”超声造影剂的合成和验证，该造影剂在与局部生化物质相互作用时变得活跃，用于乳腺肿瘤的非侵入性、准确诊断和分期。活检和组织学通常用于调查常规乳房X线检查中发现的可疑病变，因为这些程序为肿瘤的诊断和分期提供了最相关的信息。然而，活检是侵入性的，昂贵的和潜在的危险。开发一种能够可靠、廉价地对肿瘤进行成像的非侵入性工具，将有助于减少乳腺癌患者不必要的活检次数，以及相关的身体、财务和心理成本。在这项提案中，我们寻求开发高分辨率超声成像方法，以准确识别乳房X光检查中的可疑病变是否值得进一步研究或治疗，以及筛查潜在的耐药性。 超声已经成功地用于对比增强的血池成像，但是通常需要提高图像分辨率的造影剂由于其微尺度尺寸而不能在血管外空间内积聚，从而防止肿瘤的分期。通过利用亚微米造影剂可以实现更好的肿瘤穿透;不幸的是，由于较低的声散射截面和潜在的不稳定性，这些造影剂不能提供高对比度。大小和对超声的响应之间的平衡可以通过使用仅在被靶癌细胞摄取后才变得活跃的响应性造影剂来解决。在这样的方案中，可以消除来自仍然在血流中的造影剂的背景信号，并且可以相应地提高超声图像的对比度。 拟议的研究描述了纳米级超声造影剂的设计、合成和评价，该造影剂仅在细胞内谷胱甘肽（GSH）水平存在的情况下才能激活，以非侵入性地确定肿瘤预后。我们将生产二硫键交联聚合物和基于二氧化硅的外壳，它们可以被与转移性疾病和潜在耐药性相关的细胞内GSH水平消化。二硫键交联的还原将软化壳，并允许在较低的成像功率下观察这些造影剂，其中预期造影剂的ON和OFF状态之间存在很大的非线性信号差异。 PI Goodwin和合作研究者Yildirim将联合收割机结合他们的专业知识，通过完成以下具体目标来完成这项研究：1.具有GSH敏感性的氧化还原响应性单层聚合物胶囊的设计和验证; 2.用于长期监测细胞的氧化还原响应性双层聚合物胶囊的设计和验证;以及3.体外乳腺癌细胞系中GSH的定量。