Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), Department of Chemistry , Wuhan University , Wuhan 430072 , China.
Anal Chem. 2019 Aug 20;91(16):10596-10603. doi: 10.1021/acs.analchem.9b01721. Epub 2019 Jul 30.
Therapeutic drug monitoring is central to optimize therapeutic efficacy and minimize adverse events; however, the pharmacokinetics and pharmacodynamics of most drugs differ greatly among individuals. Evaluation of the therapeutic response is in urgent need to help clinician predict the clinical dose of drug. Herein, we described an analytical assay using gold nanocluster (AuNC)-decorated metal-organic frameworks (MOFs) for targeted drug delivery and monitoring pharmacodynamics, giving attractive options for studying individualized therapy. The camptothecin (Cam) anticancer drug was caged in the NH-MIL-101(Fe) MOFs. Modification with pegylated folate (FA) for specifically recognizing a FA receptor on the cancer cell membrane significantly improved the delivery efficiency. Intercellular delivery of Cam initiated programmed death of cells and upregulated the apoptosis indicator (caspase-3), which cleaved the peptide linker between AuNCs and MOFs. The quenched fluorescence of AuNCs was then recovered once the peptide was enzymatically cleaved by caspase-3. Real-time monitoring of targeted drug delivery was achieved by imaging of the light-up fluorescence in HepG2 cells, while the amount of caspase-3 could be quantified by detecting Au in the released AuNCs in inductively coupled plasma mass spectrometry (ICP-MS) with a limit of detection (LOD) of 0.12 ng mL. Our assay emphasizes the application of multifunctional nanomaterial for therapeutic self-monitoring and quantitative evaluation of therapeutic response, allowing the acceleration of drug evaluation.
治疗药物监测对于优化治疗效果和最小化不良反应至关重要；然而，大多数药物的药代动力学和药效动力学在个体之间有很大的差异。评估治疗反应是迫切需要的，以帮助临床医生预测药物的临床剂量。在此，我们描述了一种使用金纳米簇（AuNC）修饰的金属有机骨架（MOFs）进行靶向药物递送和监测药效动力学的分析方法，为研究个体化治疗提供了有吸引力的选择。喜树碱（Cam）抗癌药物被笼在 NH-MIL-101（Fe）MOFs 中。用聚乙二醇化叶酸（FA）修饰以特异性识别癌细胞膜上的 FA 受体，显著提高了递送效率。Cam 的细胞内递送引发了细胞程序性死亡，并上调了凋亡标志物（caspase-3），该标志物切割 AuNCs 和 MOFs 之间的肽连接物。一旦 caspase-3 酶切肽，AuNCs 的荧光就会被恢复。通过在 HepG2 细胞中成像点亮的荧光来实现靶向药物递送的实时监测，而通过电感耦合等离子体质谱法（ICP-MS）检测释放的 AuNCs 中的 Au 来定量检测 caspase-3，检测限（LOD）为 0.12ng mL。我们的测定强调了多功能纳米材料在治疗自我监测和治疗反应的定量评估中的应用，允许加速药物评估。
