Micellar delivery of dasatinib for the inhibition of pathologic cellular processes of the retinal pigment epithelium
Micellar delivery of dasatinib for the inhibition of pathologic cellular processes of the retinal pigment epithelium
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DOI：
10.1016/j.colsurfb.2015.12.053
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发表时间：
2016-04-01
影响因子：
5.8
通讯作者：
Lee, Thomas W. Y.
中科院分区：
文献类型：
--
作者：
Li, Qingqing;Lai, Ka Lun;Lee, Thomas W. Y.
本研究的目的是制造负载达沙替尼的纳米颗粒，并评估其抑制与增殖性玻璃体视网膜病变（PVR）相关的视网膜色素上皮（RPE）细胞过程的功效，目前尚无批准的药理学方法。我们成功地将达沙替尼（一种难溶性多靶点酪氨酸激酶抑制剂，在治疗 PVR 方面具有巨大潜力）封装到由 PEG-b-PCL 胶束制备的纳米颗粒中。纳米胶束的尺寸约为55 nm，分布较窄。他们将达沙替尼的溶解度提高了 475 倍，并提供了持续的药物释放。 ARPE-19 是一种永生的 RPE 细胞系，用于评估胶束达沙替尼的体外疗效，因为 RPE 被认为在 PVR 的发病机制中发挥着关键作用。进行了三种基于细胞的测定，即增殖、粘附和迁移，代表了 RPE 的三种重要的 PVR 相关细胞变化，并评估了胶束的细胞毒性。空白胶束和负载达沙替尼的胶束对 ARPE-19 细胞均无细胞毒性。与游离药物相比，胶束达沙替尼显着抑制细胞增殖、粘附和迁移；这可能归因于溶解度的提高。 PEG-b-PCL 胶束通过能量依赖性网格蛋白和小窝介导的内吞作用被吸收到 ARPE-19 细胞中。我们的结果表明，细胞摄取和载药胶束的抗增殖作用呈线性相关。载药量似乎是细胞摄取的关键参数，这反过来又影响聚合物胶束的体外生物活性。我们的结果清楚地表明，达沙替尼封装的胶束在 PVR 的治疗方面具有相当大的前景。 (C) 2015 Elsevier B.V. 保留所有权利。
The objective of this study was to fabricate dasatinib-loaded nanoparticles and evaluate their efficacy in inhibiting cellular processes of the retinal pigment epithelium (RPE) related to proliferative vitreoretinopathy (PVR), for which there are no approved pharmacological approaches. We successfully encapsulated dasatinib, a poorly soluble multi-targeted tyrosine kinase inhibitor which has great potential for the treatment of PVR, into nanoparticles prepared from micellation of PEG-b-PCL. The size of the nanomicelles was approximately 55 nm with a narrow distribution. They increased the solubility of dasatinib by 475x and provided a sustained drug release. ARPE-19, an immortal RPE cell line, was used to assess the in vitro efficacy of micellar dasatinib because the RPE is believed to play a key role in the pathogenesis of PVR. Three cell-based assays, namely, proliferation, adhesion and migration, which represent three important PVR-related cellular changes of the RPE, were conducted and the cytotoxicity of micelles was also evaluated. Both blank and dasatinib-loaded micelles were non-cytotoxic towards ARPE-19 cells. Micellar dasatinib significantly inhibited cell proliferation, adhesion and migration compared to the free drug; this might be attributable to enhanced solubility. PEG-b-PCL micelles were taken up into the ARPE-19 cells by an energy-dependent clatharin and caveolae-mediated endocytosis. Our results indicated that cellular uptake and the anti-proliferation effect of drugloaded micelles were linearly correlated. Drug loading appears to be a critical parameter for cellular uptake which in turn impacts the in vitro bioactivities of polymeric micelles. Our results clearly demonstrated that dasatinib-encapsulated micelles offer considerable promise in the management of PVR. (C) 2015 Elsevier B.V. All rights reserved.