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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

基本信息

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
项目类别：
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

项目摘要

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）：早期发现是根除大多数疾病的关键，尤其是癌症。磁共振成像（MRI）是一种强大的、无创的检测体内异常组织的方法。然而，目前临床批准的造影剂对癌细胞缺乏特异性，弛豫效率低下，并且可能具有细胞毒性。我们建议