Collaborative Research: Rapid Biosensing of Protein-Bound Drug Concentrations in the Body for Improved Drug Efficacy and Safety

精确医学的目标是以最大化疗效同时将副作用降至最低的方式优化每个人的药物剂量。然而，在实践中，抽血的繁琐和侵入性，以及随后实验室分析的劳动密集性，排除了剂量的个性化。面对这种情况，临床医生根据对体内药物浓度的间接估计做出剂量决定，因此往往非常不准确，导致不受欢迎的副作用和医疗保健系统每年额外的5000亿美元成本。有鉴于此，存在着对支持在护理点方便和准确地测量药物浓度的技术的主要需求，如果这种技术可以被患者在家中或工作中使用，则具有更大的价值。然而，快速测量药物浓度可能很复杂，因为大多数药物的很大一部分是与血液蛋白质结合的。该项目提出了一种基于适体的生化传感器，能够对个性化药物的蛋白质结合和非结合药物浓度进行快速、护理点测量。这项工作包括一项综合教育计划，该计划涉及本科生研究合作社的参与，重点关注代表性不足的群体。该计划的技术目标是设计和制造能够快速测量血液循环中药物的活性(未结合)和总(未结合+蛋白质结合)浓度的生化传感器装置。这项研究是基于这样一个假设，即微流控装置可以快速采集血液和间质液等生物体液的样品，并有效地变性药物的结合蛋白，从而可以通过定量的电化学适配子传感器测量药物的未结合和总(未结合+蛋白质结合)浓度。这将通过实施一种新型膜来实现，该膜保护药物检测传感器免受释放蛋白质结合药物所必需的恶劣条件的影响。具体地说，该膜对药物具有渗透性，但对从蛋白质中释放药物所需的酸和碱不会渗透，否则会损害传感器。该提案旨在推进跨膜物理、酸、碱和盐条件对传感器的影响等方面的知识，并为与体内蛋白质结合的药物的百分比提供新的线索。对药物与蛋白质结合程度的了解将导致对血液中提供治疗效果的药物未结合部分的基本知识，以及引起毒性或不想要的副作用。该技术将提供有关药物的生物利用度、毒性、干扰、新陈代谢、清除量和吸收率的信息。总的来说，建议的设备将改善患者的健康，并将降低医疗保健提供工作流程的复杂性。该奖项反映了NSF的法定使命，并已通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Precision medicine aims to optimize drug dosages for each individual in a manner that maximizes efficacy while minimizing side effects. In practice, however, the cumbersome and invasive nature of blood draws, and the labor-intensive nature of their subsequent laboratory analysis has precluded the personalization of dosing. In the face of this, clinicians base dosing decisions on indirect, and thus often highly inaccurate estimators of drug concentrations in the body, leading to undesired side effects and $500 billion in additional annual cost to the health-care system. Given this, there exists a major need for technologies supporting convenient and accurate measurement of drug concentrations at the point of care, with even greater value if such technology could be used by patients at home or work. Performing rapid measurement of drug concentrations can be complex, however, because a significant fraction of most drugs is bound to blood proteins. The project proposes an aptamer based biochemical sensor capable of performing rapid, point-of-care measurements of both protein-bound and unbound drug concentrations for personalized medicine. The work includes an integrated education plan that involves the participation of undergraduate research co-ops with a focus on underrepresented groups.The technical objective of this proposal is design and fabrication of biochemical sensor device that can rapidly measure both the active (unbound) and the total (unbound+protein bound) concentrations of drugs in blood circulation. The proposed research is based on the hypothesis that microfluidic devices can quickly sample biofluids such as blood and interstitial fluid, and efficiently denature the binding-protein for the drug such that both the unbound and total (unbound+protein-bound) drug concentrations can be measured by quantitative electrochemical aptamer sensors. This will be accomplished by implementing a novel membrane that protects the drug-detecting sensor from the harsh conditions necessary to liberate protein-bound drugs. Specifically, the membrane will be permeable to drugs but will be impermeable to acids and bases needed to release drug from proteins and which would otherwise harm the sensor. The proposal aims to advance knowledge spanning the physics of membranes, the influence of acid, base, and salt conditions on sensors, and shed new light on the percentage of drugs that are bound to proteins in the body. The understanding of how much drug is bound to proteins will lead to fundamental knowledge of the unbound portion of drug in blood that provides a therapeutic effect, as well as causes toxicity or unwanted side-effects. The technique will provide information on drug bioavailability, toxicity, interference, metabolism, clearance, and absorption rates. In general, the proposed devices will result in improved patient health and will reduce the complexity of workflow in healthcare delivery.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.