Circulating Red Blood Cell Based Nanosensors for Continuous, Real-Time Drug Monitoring

项目摘要 在这个项目中，我们将开发新的技术，为非侵入性和持续治疗药物 监测.药物剂量通常是根据人口平均数规定的，但在大多数情况下， 很少或根本不进行全身药物水平的直接临床测试。这是特别 对于治疗指数较窄的药物，治疗可能无效或完全无效， 有毒因此，持续需要用于常规药物监测的新技术，以允许 更好的治疗效果，同时最大限度地减少副作用。 我们建议通过开发药物敏感的荧光纳米传感器来解决这个问题， 使用循环红细胞（RBC）血影作为保持在循环中的载体。通过使用近- 在高局部浓度的红外荧光团，这些将产生药物依赖性信号， 可以用外部光学读取器测量。因为未经修饰的红细胞已知会留在 循环数周或数月，这将允许长期，连续监测直接在 外周血虽然这项技术有很多潜在用途，但我们将首先开发它， 监测锂和钠作为处方药及其毒副作用的例子。 该项目有三个主要阶段。首先，我们将设计荧光红细胞（f-RBC） 在血液中稳定循环的纳米传感器。这些将封装新型荧光 传感器结构用于准确定量锂和钠的血液浓度。二是 将开发一种f-RBC荧光读取器，用于非侵入性和准确定量f-RBC 无需抽取血液样本即可在体内发出信号。读片员将测量循环f-RBC 传感器位于前臂的主要血管中，采用漫反射配置。三是 在体外和大鼠的光流模型中验证和优化我们的f-RBC传感器和读取器 用锂和利尿剂治疗。 从长远来看，我们预计我们的f-RBC纳米传感器技术将有许多用途， 在许多医学领域的个性化治疗剂量监测。该技术还能够 在未来扩展到监测对下游药物靶点的影响。

PROJECT SUMMARY In this project we will develop new technology for non-invasive and continuous therapeutic drug monitoring. Drug dosing is normally prescribed based on population averages, but in most cases direct clinical testing of systemic drug levels is performed infrequently or not at all. This is particularly problematic for drugs with narrow therapeutic indices, where treatment can be ineffective or outright toxic. Therefore, there is a persistent need for new technology for routine drug monitoring to allow better therapeutic outcomes while minimizing side-effects. We propose to address this problem by developing drug-sensitive fluorescent nanosensors that will use circulating red blood cell (RBC) ghosts as a vehicle to remain in circulations. By using near- infrared fluorophores at high local concentrations, these will produce drug-dependent signals that will be measurable with an external optical reader. Because unmodified RBCs are known to stay in circulation for weeks or months, this will allow long-term, continuous monitoring directly in the peripheral blood. Although there are many potential uses for this technology, we will first develop it for monitoring lithium and sodium as examples of a prescribed drug and its toxic side-effect. The project has three main phases. First we will design fluorescent red blood cell (f-RBC) nanosensors that circulate stably in the blood stream. These will encapsulate novel fluorescent sensor constructs for accurate quantification of Lithium and sodium blood concentrations. Second, we will develop an f-RBC fluorescence reader that for non-invasive and accurate quantification of f-RBC signals in vivo without having to draw blood samples. The reader will measure circulating f-RBC sensors in major blood vessels in the forearm in diffuse reflectance configuration. Third, we will validate and optimize our f-RBC sensor and reader in optical flow-phantom models in vitro and in rats treated with lithium and a diuretic in vivo. Longer term, we anticipate that there will be many uses for our f-RBC nanosensor technology for personalized therapeutic dose monitoring in many areas of medicine. The technology could also be extended to monitor effects on downstream drug targets in the future.