Lamprecht Alf, Benoit Jean-Pierre
Laboratory of Pharmaceutical Engineering, Faculty of Medicine and Pharmacy, University of Franche-Comté, Place Saint Jacques, F-25030 Besançon Cedex, France.
J Control Release. 2006 May 15;112(2):208-13. doi: 10.1016/j.jconrel.2006.02.014. Epub 2006 Feb 28.
In cancer treatment, efficient therapeutic strategies could be impeded by cellular mechanisms such as the multidrug resistance. Recently, drug-loaded nanoparticles have been reported to be useful, since they allow entering the cancer cell and act as an intracellular anti-cancer drug reservoir. A new approach is proposed here by the use of lipid nanocapsules (LNC) which were hypothesized to reverse multidrug resistance additionally by their P-glycoprotein (P-gp) inhibiting surfactant. LNC (mean diameter 25 to 100 nm) were loaded with etoposide, tested for the drug release and their efficiency to reduce cell growth in cell culture for C6, F98, and 9L glioma cell lines. Sustained etoposide release can be provided over a period of 1 week (t10%: 1.4+/-0.1h; t50%: 15.9+/-2.8h). The P-gp inhibiting activity in-vitro was found to be independent from the LNC size. In cell culture, an internalization of LNC was observed in all glioma cell types. Etoposide LNC showed a generally higher efficiency than the drug solution while blank LNC were found to be less inhibitory than the pure drug at equivalent concentrations (IC50: C6: etoposide: 25.2 microM; LNC: 2.6-8.9 microM, F98: etoposide: 46.5 microM; LNC: 1.4-14.7 microM, 9L: etoposide: 58.2 microM; LNC: 4.4-12.7 microM). This effect was found to be particle size dependent within a range of an 8- (C6) to 33-fold (F98) increased cytotoxicity for smallest particles. When cells were incubated with etoposide solution in the presence of blank LNC, a slight growth inhibition was observed, however, distinctly lower than the drug-trapping particles. Moreover, cell toxicity on astrocytes was similar for etoposide LNC and etoposide solution. The mechanism of action of etoposide LNC was proposed to be a cell uptake followed by a sustained drug release from the LNC in combination with an intracellular P-gp inhibition ensuring a higher anticancer drug concentration inside the cancer cells.
在癌症治疗中，多药耐药等细胞机制可能会阻碍有效的治疗策略。最近，有报道称载药纳米颗粒很有用，因为它们能够进入癌细胞并作为细胞内抗癌药物储存库。本文提出了一种新方法，即使用脂质纳米胶囊（LNC），据推测其通过抑制P-糖蛋白（P-gp）的表面活性剂还能逆转多药耐药。LNC（平均直径25至100纳米）装载了依托泊苷，测试了其药物释放情况以及在细胞培养中对C6、F98和9L胶质瘤细胞系减少细胞生长的效率。依托泊苷可在1周内持续释放（t10%：1.4±0.1小时；t50%：15.9±2.8小时）。发现体外P-gp抑制活性与LNC大小无关。在细胞培养中，所有胶质瘤细胞类型均观察到LNC的内化。依托泊苷LNC通常比药物溶液具有更高的效率，而空白LNC在等效浓度下的抑制作用比纯药物小（IC50：C6：依托泊苷：25.2微摩尔；LNC：2.6 - 8.9微摩尔，F98：依托泊苷：46.5微摩尔；LNC：1.4 - 14.7微摩尔，9L：依托泊苷：58.2微摩尔；LNC：4.4 - 12.7微摩尔）。在8倍（C6）至33倍（F98）范围内，发现这种效应与颗粒大小有关，最小颗粒的细胞毒性增加。当细胞在空白LNC存在下与依托泊苷溶液一起孵育时，观察到轻微的生长抑制，然而明显低于载药颗粒。此外，依托泊苷LNC和依托泊苷溶液对星形胶质细胞的细胞毒性相似。依托泊苷LNC的作用机制被认为是细胞摄取，随后LNC持续释放药物，并结合细胞内P-gp抑制，确保癌细胞内有更高的抗癌药物浓度。
