Population pharmacokinetic modelling of indium-based quantum dot nanoparticles: preclinical in vivo studies.
Population pharmacokinetic modelling of indium-based quantum dot nanoparticles: preclinical in vivo studies.
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DOI：
10.1016/j.ejps.2020.105639
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发表时间：
2021-02-01
期刊：
影响因子：
--
通讯作者：
Della Pasqua O
中科院分区：
文献类型：
--
作者：
Yaghini E;Tacconi E;Pilling A;Rahman P;Broughton J;Naasani I;Keshtgar MRS;MacRobert AJ;Della Pasqua O
量子点(QD)纳米粒子在生物医学上的应用，特别是它们作为诊断应用的显像剂的应用，引起了人们的极大兴趣。为了研究量子点在体内的生物分布和潜在的毒性，建立药代动力学(PK)模型作为预测量子点随时间的暴露曲线的基础是至关重要的。在这里，我们研究了新的基于铟的量子点在小鼠体内的生物分布，静脉给药后长达三个月，随后开发了一个翻译种群PK模型来将研究结果扩展到人类。这项评估得到了对量子点在大鼠体内毒理学的全面概述的补充。量子点主要被肝和脾摄取，并通过肝胆和尿路排泄。采用多室PK模型，采用非线性混合效应模型描述量子点在血液和器官中的分布特征。观察到的血液和组织暴露于量子点的特点是在短期和长期具有可接受的准确性水平。值得注意的是，在注射后的第一个24小时内，量子点从血液快速分布到肝和脾中(半衰期为28分钟)，随后是一个较长的消除过程(半衰期范围：47-90天)。这是第一次使用群体药代动力学方法来分析体内临床前数据来评估量子点的PK属性的研究。在注射后24小时、1周和5周，全身注射高达48 mg/kg的量子点数，没有观察到器官损伤。结合毒理学实验产生的数据，PK参数估计提供了对人体内量子点潜在的PK特性的洞察，这最终允许预测它们的处置，并使第一个人类量子点研究的设计得以优化。
There is considerable interest in biomedical applications of quantum dot (QD) nanoparticles, in particular their use as imaging agents for diagnostic applications. In order to investigate the in vivo biodistribution and the potential toxicity of quantum dots (QDs), it is crucial to develop pharmacokinetic (PK) models as basis for prediction of QDs exposure profiles over time. Here, we investigated the in vivo biodistribution of novel indium-based QDs in mice for up to three months after intravenous administration and subsequently developed a translational population PK model to scale findings to humans. This evaluation was complemented by a comprehensive overview of the in vivo toxicology of QDs in rats. The QDs were primarily taken up by the liver and spleen and were excreted via hepatobiliary and urinary pathways. A non-linear mixed effects modelling approach was used to describe blood and organ disposition characteristics of QDs using a multi-compartment PK model. The observed blood and tissue exposure to QDs was characterised with an acceptable level of accuracy at short and long-term. Of note is the fast distribution of QDs from blood into liver and spleen in the first 24 h post-injection (half-life of 28 min) followed by a long elimination profile (half-life range: 47-90 days). This is the first study to assess the PK properties of QDs using a population pharmacokinetic approach to analyse in vivo preclinical data. No organ damage was observed following systemic administration of QDs at doses as high as 48 mg/kg at 24 h, 1 week and 5 weeks post-injection. In conjunction with the data arising from the toxicology experiments, PK parameter estimates provide insight into the potential PK properties of QDs in humans, which ultimately allow prediction of their disposition and enable optimisation of the design of first-in-human QDs studies.
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