Partlow Kathryn C, Lanza Gregory M, Wickline Samuel A
Department of Medicine, Washington University in St. Louis, School of Medicine, Campus Box 8215, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Biomaterials. 2008 Aug;29(23):3367-75. doi: 10.1016/j.biomaterials.2008.04.030. Epub 2008 May 16.
The ability to specifically deliver therapeutic agents to selected cell types while minimizing systemic toxicity is a principal goal of nanoparticle-based drug delivery approaches. Numerous cellular portals exist for cargo uptake and transport, but after targeting, intact nanoparticles typically are internalized via endocytosis prior to drug release. However, in this work, we show that certain classes of nanoparticles, namely lipid-coated liquid perfluorocarbon emulsions, undergo unique interactions with cells to deliver lipophilic substances to target cells without the need for entire nanoparticle internalization. To define the delivery mechanisms, fluorescently-labeled nanoparticles complexed with alphav beta 3-integrin targeting ligands were incubated with alphav beta 3-integrin expressing cells (C32 melanoma) under selected inhibitory conditions that revealed specific nanoparticle-to-cell interactions. We observed that the predominant mechanism of lipophilic delivery entailed direct delivery of lipophilic substances to the target cell plasma membrane via lipid mixing and subsequent intracellular trafficking through lipid raft-dependent processes. We suggest that local drug delivery to selected cell types could be facilitated by employing targeted nanoparticles designed specifically to utilize alternative membrane transport mechanisms.
在将全身毒性降至最低的同时，将治疗剂特异性递送至选定细胞类型的能力是基于纳米颗粒的药物递送方法的主要目标。存在许多用于货物摄取和运输的细胞入口，但在靶向之后，完整的纳米颗粒通常在药物释放之前通过内吞作用被内化。然而，在这项工作中，我们表明某些类型的纳米颗粒，即脂质包裹的液态全氟化碳乳液，与细胞发生独特的相互作用，将亲脂性物质递送至靶细胞，而无需整个纳米颗粒内化。为了确定递送机制，将与αvβ3整合素靶向配体复合的荧光标记纳米颗粒在选定的抑制条件下与表达αvβ3整合素的细胞（C32黑色素瘤细胞）孵育，这些条件揭示了纳米颗粒与细胞之间的特异性相互作用。我们观察到，亲脂性递送的主要机制是通过脂质混合将亲脂性物质直接递送至靶细胞质膜，并随后通过脂质筏依赖性过程进行细胞内运输。我们建议，通过使用专门设计用于利用替代膜转运机制的靶向纳米颗粒，可以促进向选定细胞类型的局部药物递送。
