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，该超声造影剂会响应与局部生化物质的相互作用而变得活跃，从而对乳腺肿瘤进行非侵入性、准确的诊断和分期。研究常规乳房X光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、昂贵的并且具有潜在危险。开发一种可以可靠的非侵入性工具。廉价的肿瘤成像将有助于减少乳腺癌患者不必要的活检数量以​​及相关的身体、经济和心理成本。在本提案中，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。值得进一步研究或治疗，并且筛查潜在的耐药性超声已成功用于对比增强血池成像，但通常需要提高图像分辨率的造影剂由于其微观尺度而无法在血管外空间内积聚。尺寸，从而防止肿瘤的分期可以通过使用亚微米造影剂来实现；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。在这种方案中，来自仍在血流中的造影剂的背景信号可以被消除，并且可以相应地改善超声图像的对比度。研究描述了纳米级材料的设计、合成和评估超声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，从而无创地确定肿瘤预后。我们将生产二硫化物交联聚合物和二氧化硅基外壳，这些外壳可被与转移性疾病相关的细胞内 GSH 水平消化。潜在的耐药性。二硫键交联的减少将使壳软化，并允许在较低的成像功率下观察这些造影剂，其中造影剂的开和关状态之间存在很大的非线性信号差异。预计 PI Goodwin 和联合研究员 Yildirim 将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. 设计和验证对 GSH 敏感的氧化还原响应单层聚合物胶囊； 2. 设计和验证对 GSH 敏感的氧化还原响应单层聚合物胶囊。用于长期监测细胞的氧化还原响应双层聚合物胶囊；以及 3. 体外乳腺癌细胞系中 GSH 的定量。