An in Vivo Nanosensor Measures Compartmental Doxorubicin Exposure
An in Vivo Nanosensor Measures Compartmental Doxorubicin Exposure
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DOI：
10.1021/acs.nanolett.9b00956
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发表时间：
2019-07-01
期刊：
影响因子：
10.8
通讯作者：
Heller, Daniel A.
中科院分区：
文献类型：
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作者：
Harvey, Jackson D.;Williams, Ryan M.;Heller, Daniel A.
药物暴露于特定器官和组织的临床前测量通常通过破坏性方法进行。组织特异性测量是重要的，特别是对于具有难治性剂量限制性毒性的药物，例如多柔比星介导的心脏毒性。我们开发了一种方法，使用可植入的光学纳米传感器，可以在手术植入后进行非侵入性询问，以快速量化阿霉素暴露于活生物体内的组织。用DNA功能化的单壁碳纳米管的近红外荧光被发现通过大而均匀的红移响应于阿霉素。我们发现这是常见的DNA嵌入剂，包括蒽环类化合物，如阿霉素。阿霉素在缓冲液和血清中，细胞内，并从表面上的单个纳米管测量。阿霉素吸附到DNA悬浮的纳米管没有取代DNA，但结合不可逆。我们将纳米传感器纳入可植入膜中，该膜允许累积检测体内多柔比星暴露。在将设备植入不同的隔室中时，例如皮下和腹膜腔内，我们实现了对注射到腹膜腔中的阿霉素的实时微创检测，以及隔室特异性测量。我们在体内测量了阿霉素穿过腹膜的移位。体内稳健的微创药代动力学测量表明该技术适用于临床前药物发现应用。
Preclinical measurements of drug exposure to specific organs and tissues is normally performed by destructive methods. Tissue-specific measurements are important, especially for drugs with intractable dose-limiting toxicities, such as doxorubicin-mediated cardiotoxicity. We developed a method to rapidly quantify doxorubicin exposure to tissues within living organisms using an implantable optical nanosensor that can be interrogated noninvasively following surgical implantation. The near-infrared fluorescence of single-walled carbon nanotubes functionalized with DNA was found to respond to doxorubicin via a large and uniform red-shift. We found this to be common to DNA-intercalating agents, including anthracycline compounds such as doxorubicin. Doxorubicin was measured in buffer and serum, intracellularly, and from single nanotubes on a surface. Doxorubicin adsorption to the DNA-suspended nanotubes did not displace DNA but bound irreversibly. We incorporated the nanosensors into an implantable membrane which allowed cumulative detection of doxorubicin exposure in vivo. On implanting the devices into different compartments, such as subcutaneously and within the peritoneal cavity, we achieved real-time, minimally invasive detection of doxorubicin injected into the peritoneal cavity, as well as compartment-specific measurements. We measured doxorubicin translocation across the peritoneal membrane in vivo. Robust, minimally invasive pharmacokinetic measurements in vivo suggest the suitability of this technology for preclinical drug discovery applications.