Smart, enzyme-activated MRI contrast agents for cancer detection

描述（由申请人提供）：早期发现是根除大多数疾病的关键，特别是癌症。磁共振成像（MRI）是一种强大的，非侵入性的方法来检测体内的异常组织。然而，目前临床上批准的造影剂缺乏对癌细胞的特异性，经历无效的弛豫，并且可能是细胞毒性的。我们提出 一种新型的“智能”MRI试剂，在癌症部位被选择性激活。对于该提议，MRI试剂将通过经由组织蛋白酶B的选择性酶水解而被“打开”，组织蛋白酶B是一种被许多癌细胞过度表达的酶。这种方法不仅大大增强了癌细胞和组织的信号强度，而且与传统的基于Gd 3+的MRI试剂相比，所提出的试剂应该具有更低的毒性并表现出更大的弛豫性。此外，所提出的代理可以在能量独立的过程中进入细胞，以提供在细胞内操作的智能MRI代理。未来的应用包括为MRI试剂配备靶向试剂，以获得更大的细胞/组织选择性。为了检测不过度表达合适酶的癌症，将连接不同类型的开关，其将响应氧化还原化学或pH的变化。该提案的具体目标是创建MRI试剂，其可以在“关闭”和“打开”模式下优化，测试它们对组织蛋白酶B的响应，测量它们的弛豫率值，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制的智能MRI试剂，以推进细胞功能的研究，并提供疾病的早期检测，如癌症。 公共卫生相关性：MRI是一种广泛使用的成像工具，用于检测体内早期癌症。结合“智能”MRI试剂，选择性地在病变组织上发光，将大大推进MRI，挽救生命，降低成本，减少衰弱。在这项提案中提出的是一种新的智能MRI药物，它在过表达组织蛋白酶B（几种癌症的生物标志物）的位点开启。长期目标是构建智能MRI试剂，以检测癌症的独特特征，例如酶表达、缺氧和酸性pH值。

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.