Department of Chemistry, University College London, London, United Kingdom.
Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, London, United Kingdom.
PLoS One. 2020 Nov 13;15(11):e0240197. doi: 10.1371/journal.pone.0240197. eCollection 2020.
We investigated how the shape of polymeric vesicles, made by the exact same material, impacts the replication activity and metabolic state of both cancer and non-cancer cell types. First, we isolated discrete geometrical structures (spheres and tubes) from a heterogeneous sample using density-gradient centrifugation. Then, we characterized the cellular internalization and the kinetics of uptake of both types of polymersomes in different cell types (either cancer or non-cancer cells). We also investigated the cellular metabolic response as a function of the shape of the structures internalized and discovered that tubular vesicles induce a significant decrease in the replication activity of cancer cells compared to spherical vesicles. We related this effect to the significant up-regulation of the tumor suppressor genes p21 and p53 with a concomitant activation of caspase 3/7. Finally, we demonstrated that combining the intrinsic shape-dependent effects of tubes with the delivery of doxorubicin significantly increases the cytotoxicity of the system. Our results illustrate how the geometrical conformation of nanoparticles could impact cell behavior and how this could be tuned to create novel drug delivery systems tailored to specific biomedical application.
我们研究了由完全相同材料制成的聚合物囊泡的形状如何影响癌症和非癌细胞类型的复制活性和代谢状态。首先，我们使用密度梯度离心从异质样品中分离出离散的几何结构（球体和管）。然后，我们表征了两种聚合物囊泡在不同细胞类型（癌症或非癌细胞）中的细胞内化和摄取动力学。我们还研究了作为内化结构形状的函数的细胞代谢反应，并发现与球体囊泡相比，管状囊泡可显著降低癌细胞的复制活性。我们将这种效应与肿瘤抑制基因 p21 和 p53 的显著上调以及 caspase 3/7 的激活相关联。最后，我们证明了将管的固有形状依赖性效应与阿霉素的递送相结合，可显著提高该系统的细胞毒性。我们的结果说明了纳米颗粒的几何构象如何影响细胞行为，以及如何调整这些构象来创建针对特定生物医学应用的新型药物递送系统。
