Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design.
Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design.
复制标题
对细胞表面靶向分子成像剂设计的机理和定量洞察。
DOI：
10.1038/srep25424
复制
发表时间：
2016
影响因子：
4.6
通讯作者：
Thurber,GregM
中科院分区：
文献类型：
--
作者：
Zhang,Liang;Bhatnagar,Sumit;Deschenes,Emily;Thurber,GregM
分子成像剂设计涉及同时优化多种探针性质。虽然几个所需的特性是直接的，包括高亲和力和低非特异性背景信号，但实际上这些特性之间存在定量权衡。这些包括血浆清除，其中快速清除降低背景信号，但可以减少靶摄取和结合，其中高亲和力化合物有时会遭受较低的稳定性或增加的非特异性相互作用。进一步使探针开发复杂化，许多最佳参数根据靶组织和成像剂性质而变化，使得经验方法或先前经验难以转化。在这里，我们专注于靶向细胞外受体的低分子量化合物，这些化合物具有成像剂的最高对比度值。我们使用一种机械的方法来提供一个定量的框架来权衡分子之间的权衡。我们的研究结果表明，特定的目标摄取是很好地描述了各种靶向剂的定量模拟，而非特异性的背景信号是更难以预测。比较了两种用于估计体内背景信号的体外实验方法-非特异性细胞摄取和血浆蛋白结合。总之，这些数据提供了一种定量方法来指导探针设计和集中动物工作，以更具有成本效益和时间效益的分子成像剂的发展。
Molecular imaging agent design involves simultaneously optimizing multiple probe properties. While several desired characteristics are straightforward, including high affinity and low non-specific background signal, in practice there are quantitative trade-offs between these properties. These include plasma clearance, where fast clearance lowers background signal but can reduce target uptake and binding, where high affinity compounds sometimes suffer from lower stability or increased non-specific interactions. Further complicating probe development, many of the optimal parameters vary depending on both target tissue and imaging agent properties, making empirical approaches or previous experience difficult to translate. Here, we focus on low molecular weight compounds targeting extracellular receptors, which have some of the highest contrast values for imaging agents. We use a mechanistic approach to provide a quantitative framework for weighing trade-offs between molecules. Our results show that specific target uptake is well-described by quantitative simulations for a variety of targeting agents, whereas non-specific background signal is more difficult to predict. Twoin vitroexperimental methods for estimating background signalin vivoare compared – non-specific cellular uptake and plasma protein binding. Together, these data provide a quantitative method to guide probe design and focus animal work for more cost-effective and time-efficient development of molecular imaging agents.