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

基于循环红细胞的纳米传感器，用于连续、实时药物监测

基本信息

批准号：
10062973
负责人：
Heather A Clark
金额：
$ 34.62万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062973
关键词：
Address Affect Amiloride Animals Antipsychotic Agents Area Biodistribution Blood Blood Cells Blood Circulation Blood Vessels Blood Volume Blood specimen Calibration Cavia Cells Chemistry Concentration measurement Dangerousness Detection Development Devices Diffuse Disease model Diuretics Dose Drug Kinetics Drug Monitoring Drug Prescriptions Drug Targeting Encapsulated Equilibrium Erythrocytes Excretory function Exhibits Flow Cytometry Fluorescence Forearm Future Geometry Goals Human Immune response Implant Individual Intercellular Fluid Ions Light Lithium Lithium Carbonate Measurable Measurement Measures Medicine Metabolism Monitor Mus Optical Readers Optics Outcome Patients Pharmaceutical Preparations Phase Population Problem Solving Property Rattus Reader Reporting Research Safety Sampling Side Signal Transduction Skin Sodium Stream System Techniques Technology Testing Therapeutic Therapeutic Index Time Tissues Toxic effect Translations Validation Weight absorption base biomaterial compatibility design disorder control dosage drug discovery drug-sensitive fluorophore in vitro Model in vivo innovative technologies insight nanosensors new technology novel peripheral blood personalized therapeutic phantom model ratiometric research clinical testing response salt sensitive sensor sensor technology side effect signal processing small molecule therapy outcome

项目摘要

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.

项目摘要在这个项目中，我们将开发用于非侵入性和连续治疗药物的新技术监视。药物给药通常是根据人口平均值规定的，但在大多数情况下全身药物水平的直接临床测试很少或根本不进行。尤其是对于患有狭窄治疗指数的药物的问题，治疗可能无效或直接治疗有毒的。因此，持续需要新技术来进行常规药物监测以允许更好的治疗结果，同时最小化副作用。我们建议通过开发对药物敏感的荧光纳米传感器来解决这个问题使用循环的红细胞（RBC）幽灵作为循环中的媒介。通过接近 - 红外荧光团在高局部浓度下，这些将产生依赖药物的信号使用外部光学读取器可衡量。因为已知未修改的RBC留在循环数周或几个月，这将允许直接在外周血。尽管该技术有许多潜在用途，但我们将首先开发它监测锂和钠作为处方药及其有毒副作用的例子。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。这些将封装新的荧光传感器构建体，以准确定量锂和钠血液浓度。第二，我们将开发F-RBC荧光读取器，该读取器用于非侵入性和精确定量F-RBC 体内信号无需抽血。读者将测量循环F-RBC 弥漫性反射率构型中前臂主要血管中的传感器。第三，我们会的在体外和大鼠中验证和优化我们的F-RBC传感器和读取器用锂和利尿剂在体内处理。从长远来看，我们预计我们的F-RBC纳米传感器技术将有很多用途许多医学领域的个性化治疗剂量监测。该技术也可能是扩展以监测将来对下游药物靶标的影响。