Smart, enzyme-activated MRI contrast agents for cancer detection

描述(申请人提供)：早期发现是根除大多数疾病，特别是癌症的关键。磁共振成像(MRI)是一种强大的、非侵入性的方法，可以检测体内的异常组织。然而，目前临床批准的造影剂缺乏对癌细胞的特异性，松弛效率低，而且可能具有细胞毒性。我们建议 一种新的“智能”核磁共振试剂，可以在癌症部位选择性地激活。在这项提议中，核磁共振试剂将通过组织蛋白酶B选择性的酶解来启动，组织蛋白B是一种被许多癌细胞过度表达的酶。与传统的Gd3+核磁共振试剂相比，这种方法不仅可以大大增强癌症细胞和健康组织上的信号强度，而且毒性更小，松弛程度更大。此外，所提出的试剂可以以一种能量独立的过程进入细胞，从而获得在细胞内工作的智能MRI试剂。未来的应用包括为MRI试剂配备靶向试剂，以提高细胞/组织的选择性。为了检测不过度表达合适的酶的癌症，将连接不同类型的开关，这些开关将对氧化还原化学或pH变化做出反应。这项计划的具体目标是创造可在“关”和“开”模式下优化的核磁共振试剂，测试它们对组织蛋白酶B的反应，测量它们的松弛系数，并确定它们在细胞和小鼠中的毒性。长期目标是为研究人员和医学界提供量身定做的智能MRI代理，以推进细胞功能的研究，并提供癌症等疾病的早期检测。 与公共卫生相关：核磁共振是一种广泛使用的成像工具，可以在体内的早期阶段检测癌症。结合“智能”核磁共振试剂，选择性地在病变组织上发光，将极大地促进核磁共振，拯救生命，降低成本，并减少虚弱。在这项提案中提出了一种新的智能核磁共振试剂，这种药物在表达组织蛋白B的部位启动，组织蛋白B是几种癌症的生物标记物。长期目标是构建智能核磁共振试剂，检测癌症的独特特征，如酶表达、缺氧和酸性pH。

DESCRIPTION (provided by applicant): Early detection is key to eradicating most diseases, especially cancers. Magnetic Resonance Imaging (MRI) is a powerful, noninvasive method to detect aberrant tissues within the body. Current clinically approved contrast agents, however, lack specificity for cancer cells, undergo inefficient relaxivity, and can be cytotoxic. We propose a new class of "smart" MRI agents that become activated selectively at cancer sites. For this proposal, the MRI agents will be turned "on" through selective enzymatic hydrolysis via cathepsin B, an enzyme that is overexpressed by many cancer cells. Not only will this method greatly enhance the intensity of the signal at cancerous over healthy cells and tissues, but the proposed agents should be less toxic and demonstrate greater relaxivity as compared to traditional Gd3+ based MRI agents. Furthermore, the proposed agents could enter cells in an energy independent process to give smart MRI agents that operate within cells. Future applications include equipping the MRI agents with targeting agents for greater cell/tissue selectivity. To detect cancers that do not overexpress suitable enzymes, different types of switches will be attached that will respond to redox chemistry or changes in pH. The specific aims of this proposal are to create MRI agents, which can be optimized in the "off" and "on" modes, test their response to cathepsin B, measure their relaxivity values, and to determine their toxicities in cells and mice. The long-term goal is to provide researchers and the medical community tailor made smart MRI agents to advance the study of cellular functions and provide early detection of diseases, such as cancer. PUBLIC HEALTH RELEVANCE: MRI is a widely used imaging tool to detect cancers at early stages within the body. Combining "smart" MRI agents that light up selectively at diseased tissues would greatly advance MRI, saving lives, reducing costs, and reducing debilitation. Presented in this proposal is a new class of smart MRI agents that turn on at sites that over express cathepsin B, a biomarker of several cancers. The long-term goal is to construct smart MRI agents that detect the unique features of cancers, such as enzyme expression, hypoxia, and acidic pH.