Ultrasound and microbubble mediated drug delivery: Acoustic pressure as determinant for uptake via membrane pores or endocytosis
Ultrasound and microbubble mediated drug delivery: Acoustic pressure as determinant for uptake via membrane pores or endocytosis
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DOI：
10.1016/j.jconrel.2014.10.031
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发表时间：
2015-01-10
影响因子：
10.8
通讯作者：
Lentacker, Ine
中科院分区：
文献类型：
--
作者：
De Cock, Ine;Zagato, Elisa;Lentacker, Ine
虽然在超声介导的药物输送中取得了可喜的成果，但其潜在的生物物理机制仍有待阐明。在超声应用过程中已经报道了孔形成以及内吞作用。由于文献中使用的超声设置过多，因此很难得出实际涉及哪种机制的结论。据我们所知，我们是第一个表明，声压影响药物摄取的途径是解决，通过诱导不同的微泡细胞相互作用。为了研究这一点，使用FITC-葡聚糖作为模型药物，并通过流式细胞术分析其摄取。在荧光强度图中，两个亚群出现在超声应用后具有FITC-葡聚糖摄取的细胞中，对应于具有低或高摄取的细胞。通过FACS分选分离亚群后，共聚焦图像表明低摄取群体显示内吞摄取。高吸收群体代表通过孔隙的吸收。此外，随着声压的增加，亚群的分布向高摄取群体转移。超声过程中的实时共聚焦记录显示，微泡引起的膜变形可能是通过机械刺激细胞骨架引起内吞作用的触发因素。孔的形成被证明是由微泡推向细胞。这些结果提供了一个更好的洞察在微泡细胞相互作用的声压的作用和药物摄取的可能后果。此外，它指出需要一个更合理的，微泡行为为基础的超声介导的药物释放实验中的声学参数的选择。(C)2014爱思唯尔有限公司版权所有。
Although promising results are achieved in ultrasound mediated drug delivery, its underlying biophysical mechanisms remain to be elucidated. Pore formation as well as endocytosis has been reported during ultrasound application. Due to the plethora of ultrasound settings used in literature, it is extremely difficult to draw conclusions on which mechanism is actually involved. To our knowledge, we are the first to show that acoustic pressure influences which route of drug uptake is addressed, by inducing different microbubble-cell interactions. To investigate this, FITC-dextrans were used as model drugs and their uptake was analyzed by flow cytometry. In fluorescence intensity plots, two subpopulations arose in cells with FITC-dextran uptake after ultrasound application, corresponding to cells having either low or high uptake. Following separation of the subpopulations by FACS sorting, confocal images indicated that the low uptake population showed endocytic uptake. The high uptake population represented uptake via pores. Moreover, the distribution of the subpopulations shifted to the high uptake population with increasing acoustic pressure. Real-time confocal recordings during ultrasound revealed that membrane deformation by microbubbles may be the trigger for endocytosis via mechanostimulation of the cytoskeleton. Pore formation was shown to be caused by microbubbles propelled towards the cell. These results provide a better insight in the role of acoustic pressure in microbubble-cell interactions and the possible consequences for drug uptake. In addition, it pinpoints the need for a more rational, microbubble behavior based choice of acoustic parameters in ultrasound mediated drug delivery experiments. (C) 2014 Elsevier B.V. All rights reserved.