Xu Peisheng, Gullotti Emily, Tong Ling, Highley Christopher B, Errabelli Divya R, Hasan Tayyaba, Cheng Ji-Xin, Kohane Daniel S, Yeo Yoon
Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907, USA.
Mol Pharm. 2009 Jan-Feb;6(1):190-201. doi: 10.1021/mp800137z.
We reexamined the cellular drug delivery mechanism by poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) to determine their utility and limitations as an intracellular drug delivery system. First, we prepared PLGA NPs which physically encapsulated Nile red (a hydrophobic fluorescent dye), in accordance with the usual procedure for labeling PLGA NPs, incubated them with mesothelial cells, and observed an increase in the intracellular fluorescence. We then prepared NPs from PLGA chemically conjugated to a fluorescent dye and observed their uptake by the mesothelial cells using confocal microscopy. We also used coherent anti-Stokes Raman scattering (CARS) microscopy to image cellular uptake of unlabeled PLGA NPs. Results of this study coherently suggest that PLGA NPs (i) are not readily taken up by cells, but (ii) deliver the payload to cells by extracellular drug release and/or direct drug transfer to contacting cells, which are contrasted with the prevalent view. From this alternative standpoint, we analyzed cytotoxicities of doxorubicin and paclitaxel delivered by PLGA NPs and compared with those of free drugs. Finally, we revisit previous findings in the literature and discuss potential strategies to achieve efficient drug delivery to the target tissues using PLGA NPs.
我们重新审视了聚乳酸-羟基乙酸共聚物纳米颗粒（PLGA NPs）的细胞药物递送机制，以确定其作为细胞内药物递送系统的效用和局限性。首先，我们按照标记PLGA NPs的常规程序制备了物理包裹尼罗红（一种疏水性荧光染料）的PLGA NPs，将它们与间皮细胞一起孵育，并观察到细胞内荧光增加。然后，我们用化学方法将荧光染料与PLGA偶联制备纳米颗粒，并使用共聚焦显微镜观察间皮细胞对它们的摄取。我们还使用相干反斯托克斯拉曼散射（CARS）显微镜对未标记的PLGA NPs的细胞摄取进行成像。这项研究的结果一致表明，PLGA NPs（i）不容易被细胞摄取，但（ii）通过细胞外药物释放和/或药物直接转移至接触的细胞将有效载荷递送至细胞，这与普遍观点形成对比。从这个不同的角度，我们分析了PLGA NPs递送的阿霉素和紫杉醇的细胞毒性，并与游离药物的细胞毒性进行了比较。最后，我们重新审视了文献中的先前发现，并讨论了使用PLGA NPs实现向靶组织有效药物递送的潜在策略。
