Hollow Silica-Polymer Nanocomposites for Stimulus-Responsive Ultrasound Contrast

 描述(由申请人提供)：本提案描述了“智能”超声造影剂的合成和验证，这些造影剂在与局部生物化学物质相互作用时变得活跃，用于非侵入性、准确地诊断和分期乳腺肿瘤。活检和组织学检查通常是为了调查常规乳房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，活组织检查是侵入性的，成本高昂，而且有潜在的危险。开发一种能够可靠且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数量以及相关的身体、经济和心理成本。在这项建议中，我们寻求开发高分辨率的超声成像方法，以准确地识别乳房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。超声已成功地用于对比剂增强血池成像，但通常需要提高图像分辨率的造影剂由于其微尺度尺寸而无法在血管外空间内积聚，从而阻止了肿瘤的分期。利用亚微米造影剂可以获得更好的肿瘤穿透性；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。大小和对超声波的反应之间的平衡可以通过使用响应性造影剂来解决，这些造影剂只有在被靶癌细胞摄取后才变得活跃。在这种方案中，可以消除来自仍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。这项拟议的研究描述了纳米级超声造影剂的设计、合成和评价，这些造影剂只能在细胞内谷胱甘肽(GSH)存在的情况下激活，以非侵入性方式确定肿瘤预后。我们将生产二硫化物交联聚合物和二氧化硅为基础的外壳，可以被细胞内与转移性疾病和潜在的耐药性相关的GSH水平所消化。二硫键的减少将软化壳层，并允许在较低的成像功率下观察这些造影剂，因为在这种情况下，造影剂的开和关状态之间的非线性信号差异很大。Pi Goodwin和合作研究员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型单层聚合物胶囊；2.设计和验证用于长期监测细胞的氧化还原响应型双层聚合物胶囊；以及3.体外测定乳腺癌细胞中GSH的含量。

 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.