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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.

项目总结在这个项目中，我们将开发非侵入性和连续性治疗药物的新技术监控。药物剂量通常是根据人口平均水平开出的，但在大多数情况下对全身药物水平的直接临床测试很少进行，甚至根本不进行。这是特别的对于治疗指数很窄的药物来说是有问题的，治疗可能无效或完全无效有毒的。因此，对常规药物监测的新技术的持续需求更好的治疗效果，同时将副作用降至最低。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中的红细胞(RBC)幽灵作为保持循环的载体。通过使用近乎- 在高局部浓度的红外荧光团，这些将产生药物依赖的信号，将可使用外置光学读取器进行测量。因为已知未经修饰的红细胞会留在几周或几个月的循环，这将允许长期、连续地直接监测外周血液。虽然这项技术有许多潜在的用途，但我们首先将为监测锂和钠作为处方药的例子及其毒副作用。该项目分为三个主要阶段。首先，我们将设计荧光红细胞(f-RBC)。在血流中稳定循环的纳米传感器。这些将封装新的荧光传感器可用于准确量化锂和钠的血液浓度。第二，我们将开发一种f-RBC荧光读取器，用于非侵入性和准确的f-RBC定量在体内的信号，而不需要提取血液样本。阅读器将测量循环中的f-RBC 前臂主要血管中的传感器呈漫反射配置。第三，我们将在体外和大鼠的光流模型中验证和优化我们的f-RBC传感器和读取器体内用锂和利尿剂治疗。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多个医学领域的个性化治疗剂量监测。这项技术也可能是扩展到未来监测对下游药物靶点的影响。