Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan, ROC.
J Control Release. 2010 Aug 17;146(1):152-9. doi: 10.1016/j.jconrel.2010.05.023. Epub 2010 May 23.
It has been reported that nanoparticles (NPs) prepared by hydrophobically-modified polymers could accumulate passively in the tumor tissue; however, their cellular uptake mechanism and intercellular trafficking pathway have never been understood. This study was designed to address these concerns, using NPs prepared by a hydrophobically-modified chitosan (N-palmitoyl chitosan, NPCS). Molecular dynamic simulations found that a degree of substitution (DS) of 5% of palmitoyl groups on its backbone was sufficient to allow NPCS to form NPs, due to a significant increase in the intra- and intermolecular hydrophobic interactions. With an increase of DS, there were more palmitoyl groups present on the surface of NPs which were then able to interact with the cell membranes. A greater extent of cellular uptake of NPCS NPs was observed with increasing the DS on NPCS. The internalization of NPCS NPs was clearly related with the lipid raft-mediated routes; with increasing the DS on NPCS, the caveolae-mediated endocytosis became more important. The results obtained in the intracellular trafficking study showed that NPCS NPs entered cells via caveolae and transiently localized to caveosomes before trafficking to the endosomal pathway. These results suggest that the prepared NCPS NPs may serve as a carrier for intracellular delivery of therapeutic agents.
据报道，通过疏水改性聚合物制备的纳米颗粒（NPs）可以被动地在肿瘤组织中积累；然而，它们的细胞摄取机制和细胞内转运途径从未被理解。本研究旨在通过使用疏水改性壳聚糖（N-棕榈酰壳聚糖，NPCS）制备的 NPs 来解决这些问题。分子动力学模拟发现，由于分子内和分子间疏水力的显著增加，其主链上的 5%取代度的棕榈酰基足以允许 NPCS 形成 NPs。随着取代度的增加，更多的棕榈酰基存在于 NPs 的表面，然后能够与细胞膜相互作用。随着 NPCS 上 DS 的增加，观察到 NPCS NPs 的细胞摄取程度增加。NPCS NPs 的内化与脂筏介导的途径密切相关；随着 NPCS 上 DS 的增加，小窝介导的内吞作用变得更加重要。细胞内转运研究的结果表明，NPCS NPs 通过小窝进入细胞，并在转运到内体途径之前短暂定位于小窝体。这些结果表明，所制备的 NCPS NPs 可以作为治疗剂细胞内递药的载体。
