Key Lab of Industrial Biocatalysis, Ministry of Education, Department of Chemical Engineering, Tsinghua University , Beijing, 100084, China.
Mol Pharm. 2017 Dec 4;14(12):4618-4627. doi: 10.1021/acs.molpharmaceut.7b00726. Epub 2017 Nov 13.
Nanoparticles (NPs) are widely studied as tumor targeted vehicles. The penetration of NPs into the tumor is considered as a major barrier for delivery of NPs into tumor cell and a big challenge to translate NPs from lab to the clinic. The objective of this study is to know how the surface charge of NPs, the protein corona surrounding the NPs, and the fluid flow around the tumor surface affect the penetration and accumulation of NPs into the tumor, through in vitro penetration study based on a spheroid-on-chip system. Surface decorated polystyrene (PS) NPs (100 nm) carrying positive and negative surface charge were loaded to the multicellular spheroids under static and flow conditions, in the presence or absence of serum proteins. NP penetration was investigated by confocal laser microscopy scanning followed with quantitative image analysis. The results reveal that negatively charged NPs are attached more on the spheroid surface and easier to penetrate into the spheroids. Protein corona, which is formed surrounding the NPs in the presence of serum protein, changes the surface properties of the NPs, weakens the NP-cell affinity, and, therefore, results in lower NP concentration on the spheroid surface but might facilitate deeper penetration. The exterior fluid flow enhances the interstitial flow into the spheroid, which benefits the penetration but also strips the NPs (especially the NPs with protein corona) on the spheroid surface, which decreases the penetration flux significantly. The maximal penetration was obtained by applying negatively charged NPs without protein corona under the flow condition. We hope the present study will help to understand the spatiotemporal performance of drug delivery NPs and inform the rational design of NPs with highly defined drug accumulation localized at a target site.
纳米颗粒（NPs）被广泛研究作为肿瘤靶向载体。 NPs 进入肿瘤被认为是将 NPs 递送到肿瘤细胞中的主要障碍，也是将 NPs 从实验室转化为临床的一大挑战。本研究的目的是了解 NPs 的表面电荷、围绕 NPs 的蛋白质冠层以及肿瘤表面周围的流体流动如何影响 NPs 进入肿瘤的渗透和积累，通过基于球体芯片系统的体外渗透研究来实现。在存在或不存在血清蛋白的情况下，将带正电荷和负电荷的表面修饰聚苯乙烯（PS）NPs（100nm）加载到多细胞球体中，在静态和流动条件下进行。通过共聚焦激光扫描显微镜扫描并进行定量图像分析来研究 NP 的渗透。结果表明，带负电荷的 NPs 更容易附着在球体表面上并更容易渗透到球体中。蛋白质冠层在存在血清蛋白的情况下围绕 NPs 形成，改变了 NPs 的表面性质，削弱了 NP-细胞亲和力，因此导致球体表面上的 NP 浓度降低，但可能促进更深的渗透。外部流体流动增强了间质流到球体中，这有利于渗透，但也会从球体表面剥离 NPs（尤其是带有蛋白质冠层的 NPs），这会显著降低渗透通量。在流动条件下应用不带蛋白质冠层的带负电荷的 NPs 可获得最大的渗透。我们希望本研究将有助于理解药物传递 NPs 的时空性能，并为在目标部位高度集中药物积累的 NPs 的合理设计提供信息。
