Seconds-resolved pharmacokinetic measurements of the chemotherapeutic irinotecan in situ in the living body
Seconds-resolved pharmacokinetic measurements of the chemotherapeutic irinotecan in situ in the living body
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DOI：
10.1039/c9sc01495k
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发表时间：
2019-09-21
期刊：
影响因子：
8.4
通讯作者：
Plaxco, Kevin W.
中科院分区：
文献类型：
--
作者：
Idili, Andrea;Arroyo-Curras, Netzahualcoyotl;Plaxco, Kevin W.
快速实时测量体内药物的能力将促进我们对药代动力学的理解，以及我们最佳剂量和提供药物治疗的能力。为此，我们正在开发基于电化学适配体（E-AB）的传感器，这是一种秒分辨平台技术，对于在体内进行测量至关重要，它是无试剂的，可逆的，并且在直接放置在体液中时具有足够的选择性。在这里，我们描述了一种针对伊立替康的E-AB传感器的开发，伊立替康是喜树碱家族的一员，用于癌症化疗，以及它对体内传感的适应性。为了实现这一目标，我们首先重新设计（通过截断）先前报道的针对喜树碱的DNA适体，以支持高增益E-AB信号传导。然后，我们将修饰的适体与输出与目标浓度无关的非结构化氧化还原报告修饰的DNA序列共同沉积，使传感器的信号增益具有足够强的方波频率函数，以支持动力学微分测量漂移校正。该传感器直径200亩，长3毫米，放置在活体大鼠的颈静脉中，可实现20秒分辨率、多小时的血浆伊立替康测量，从而为这类化疗药物的药代动力学提供前所未有的高精度视图。
The ability to measure drugs in the body rapidly and in real time would advance both our understanding of pharmacokinetics and our ability to optimally dose and deliver pharmacological therapies. To this end, we are developing electrochemical aptamer-based (E-AB) sensors, a seconds-resolved platform technology that, as critical for performing measurements in vivo, is reagentless, reversible, and selective enough to work when placed directly in bodily fluids. Here we describe the development of an E-AB sensor against irinotecan, a member of the camptothecin family of cancer chemotherapeutics, and its adaptation to in vivo sensing. To achieve this we first re-engineered (via truncation) a previously reported DNA aptamer against the camptothecins to support high-gain E-AB signaling. We then co-deposited the modified aptamer with an unstructured, redox-reporter-modified DNA sequence whose output was independent of target concentration, rendering the sensor's signal gain a sufficiently strong function of square-wave frequency to support kinetic-differential-measurement drift correction. The resultant, 200 mu m-diameter, 3 mm-long sensor achieves 20 s-resolved, multi-hour measurements of plasma irinotecan when emplaced in the jugular veins of live rats, thus providing an unprecedentedly high-precision view into the pharmacokinetics of this class of chemotherapeutics.