Bio-electrochemical detectors for in vivo continuous monitoring

摘要我们的首要目标是使治疗药物监测方便和高度时间分辨率 因为连续葡萄糖监测仪已经提供了血糖的监测。实现这一目标将 改变了生物医学研究和临床实践的许多方面。例如，它将使 基于患者准确确定的而不是预测不佳的药物代谢的个性化给药， 这一结果与感染性疾病的治疗高度相关，感染性疾病通常使用以下药物： 危险狭窄的治疗指数，并改善妇女的健康，因为药代动力学的性别差异 导致女性中不良药理学结果加倍。最终，这种技术可以 使反馈控制的药物剂量，这通过在真实的时间响应代谢变化，将改善 具有剂量限制性毒性的药物的安全性和有效性。然而，要实现我们的目标， 两项重大创新：（1）能够在肠液中原位监测任意药物分子的技术 (ISF)（2）大大提高了关于药物代谢动力学的知识， ISF中的药物与血浆中观察到的药代动力学相关。根据上一轮的赠款资金，我们 实现了这些必要进步中的第一个。具体来说，我们证明了微创 基于适配体的电化学（EAB）传感器支持秒级分辨的实时药物测量 在我们的活体大鼠动物的血浆（静脉）、脑脊液（脑）和ISF（皮下空间）中原位 模型在这里，我们提出解决第二个创新。也就是说，使用静脉和皮下EAB 我们提出的传感器，以促进血浆和ISF药代动力学之间的关系的理解 在各种各样的抗微生物和免疫抑制剂药物中，治疗药物监测是一项 护理标准的重要组成部分。我们认为，由此产生的数量级改善， 测量这些关系是我们实现高精度渲染长期目标的关键一步 治疗药物监测方便且成本有效。

Summary. Our overarching goal is to render therapeutic drug monitoring as convenient and highly time resolved as the continuous glucose monitor has rendered the monitoring of blood sugar. The realization of this goal would transform many aspects of both biomedical research and clinical practice. It would, for example, enable personalized dosing based on a patient’s accurately determined, rather than poorly predicted, drug metabolism, an outcome of high relevance to the treatment of infectious diseases, which commonly employs drugs of dangerously narrow therapeutic index, and to improving women’s health, as pharmacokinetic sex differences lead to a doubling of adverse pharmacotherapeutic outcomes in females. Ultimately such a technology could enable feedback-controlled drug dosing, which, by responding in real time to metabolic variations, would improve the safety and efficacy of drugs that suffer from dose-limiting toxicity. To achieve our goal, however, requires two significant innovations: (1) a technology able to monitor arbitrary drug molecules in situ in the intestinal fluid (ISF) of the subcutaneous space and (2) vastly improved knowledge regarding how the pharmacokinetics of drugs in the ISF relate to the pharmacokinetics seen in plasma. Under the prior round of grant funding, we achieved the first of these necessary advances. Specifically, we demonstrated that minimally-invasive Electrochemical, Aptamer-Based (EAB) sensors support the seconds-resolved, real-time measurement of drugs in situ in the plasma (venous), cerebrospinal fluid (brain), and ISF (subcutaneous space) of our live rat animal model. Here we propose to tackle the second innovation. That is, using intravenous and subcutaneous EAB sensors we propose to advance understanding of the relationships between plasma and ISF pharmacokinetics across a diverse set of antimicrobial and immunosuppressant drugs for which therapeutic drug monitoring is an important element of the standard of care. We believe the resulting orders of magnitude improvement in measuring these relationships is a critical step towards our long-range goal of rendering high-precision therapeutic drug monitoring convenient and cost effective.