Smart, enzyme-activated MRI contrast agents for cancer detection

用于癌症检测的智能酶激活 MRI 造影剂

• 批准号: 8302566
• 负责人: DAVID B SMITHRUD
• 金额: $ 15.7万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302566
• 关键词: Animals; Architecture; Binding; Biocompatible Materials; Biological; Biological Assay; Biological Markers; Biological Testing; Biomedical Research; Cancer Detection; Cancerous; Cathepsins B; Cations; Cell Line; Cell physiology; Cells; Chemistry; Choristoma; Clinic; Clinical; Communities; Complex; Contrast Media; Data; Detection; Development; Diagnostic; Disease; Early Diagnosis; Enzymes; Exploratory/Developmental Grant; Funding Mechanisms; Future; Future Generations; Gadolinium; Goals; Hydrolysis; Hypoxia; Image; Imaging Device; Interdisciplinary Study; Lead; Light; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Medical; Medicine; Metals; Methods; Modeling; Molecular Biology; Monitor; Mus; NMR Spectroscopy; Ovarian; Oxidation-Reduction; Peptides; Physiologic pulse; Predisposition; Process; Property; Prostate; Protons; Recovery; Research; Research Personnel; Resolution; Resources; Rotaxanes; Series; Signal Transduction; Site; Solutions; Specificity; Staging; Structure; Testing; Tissues; Toxic effect; Toxicity Tests; Training; Translations; Treatment Efficacy; Water; Work; aqueous; base; cancer cell; cancer imaging; cancer site; cost; cytotoxic; design; disease diagnosis; functional group; gadolinium oxide; improved; innovation; interest; metal complex; molecular imaging; neoplastic cell; novel; overexpression; research and development; response; tumor; tumor growth

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.

描述（由申请人提供）：早期发现是消除大多数疾病，尤其是癌症的关键。磁共振成像（MRI）是一种强大的无创方法，可检测体内异常组织。然而，当前经过临床认可的对比剂缺乏对癌细胞的特异性，其效率低下，并且可能是细胞毒性的。我们建议 一类新的“智能” MRI代理在癌症部位有选择地激活。对于此提案，MRI剂将通过Catherepsin b的选择性酶水解“ ON”打开，这是一种被许多癌细胞过表达的酶。与传统的基于GD3+的MRI剂相比，这种方法不仅会大大增强癌细胞和组织上癌细胞的信号强度，而且所提出的药物应具有更大的毒性，并表现出更大的松弛性。此外，提出的代理可以在能量独立的过程中输入细胞，以使智能MRI代理在细胞内运行。未来的应用包括将MRI剂配备靶向剂，以提高细胞/组织选择性。为了检测不过表达合适酶的癌症，将附着不同类型的开关，以响应氧化还原化学或pH的变化。该提案的具体目的是创建MRI剂，可以在“ OFF”和“在”模式下进行优化，测试其对组织蛋白酶B的反应，测量其放松性值并确定其在细胞和小鼠中的毒性。长期的目标是为研究人员和医学界量身定制的量身定制，使聪明的MRI代理商推进了细胞功能的研究，并提供了癌症等疾病的早期发现。 公共卫生相关性：MRI是一种广泛使用的成像工具，可在体内早期阶段检测癌症。将“智能” MRI代理结合在一起，在患病的组织中有选择地点亮，可以大大提高MRI，挽救生命，降低成本并减少衰弱。该提案中提出的是一类新的Smart MRI代理，它们会在越过几种癌症的生物标志物的网站上打开。长期目标是构建智能MRI剂，以检测癌症的独特特征，例如酶表达，缺氧和酸性pH。