Etoposide nanocarriers suppress glioma cell growth by intracellular drug delivery and simultaneous P-glycoprotein inhibiltion
Etoposide nanocarriers suppress glioma cell growth by intracellular drug delivery and simultaneous P-glycoprotein inhibiltion
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DOI：
10.1016/j.jconrel.2006.02.014
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发表时间：
2006-05-15
影响因子：
10.8
通讯作者：
Benoit, JP
中科院分区：
文献类型：
--
作者：
Lamprecht, A;Benoit, JP
在癌症治疗中，有效的治疗策略可能会受到多药耐药等细胞机制的阻碍。最近，载药纳米颗粒被报道是有用的，因为它们允许进入癌细胞，并作为细胞内抗癌药物储存库。这里提出了一种新的方法，利用脂纳米胶囊(LNC)，它被认为是通过其P-糖蛋白(P-gp)抑制表面活性来逆转多药耐药性的。将平均直径为25~100 nm的LNC负载依托泊苷，在C6、F98和9L胶质瘤细胞系的细胞培养中检测药物释放和抑制细胞生长的效率。依托泊苷的缓释可持续1周(t(10%)：1.4+/-0.1h；t(50%)：15.9+/-2.8h)。体外P-gp抑制活性与LNC的大小无关。在细胞培养中，在所有类型的胶质瘤细胞中都观察到LNC的内化。依托泊苷LNC的药效总体上高于药物溶液，而空白LNC的抑制率在相同浓度下低于纯药物(IC50：C6：依托泊苷：25.2mU；LNC：2.6~8.9mU；F98：依托泊苷：46.5mU；LNC：1.4~14.7mU，9L：依托泊苷：58.2mU；LNC：4.4~12.7mU)。这种效应被发现在8-(C6)到33倍(1798)的范围内与颗粒大小有关，对最小颗粒的细胞毒性增加。当依托泊苷溶液与空白LNC共同孵育时，细胞的生长受到轻微的抑制，但明显低于药物捕获颗粒。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作用相似。依托泊苷LNC的作用机制被认为是细胞摄取，随后药物从LNC持续释放，并结合细胞内P-gp抑制，确保癌细胞内有较高的抗癌药物浓度。(C)2006爱思唯尔B.V.保留所有权利。
In cancer treatment, efficient therapeutic strategies could be impeded by cellular mechanisms such as the multidrug resistance. Recently, drugloaded nanoparticles have been reported to be useful, since they allow entering the cancer cell and act as an intracelluilar 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 (t(10%): 1.4 +/- 0.1 h; t(50%): 15.9 +/- 2.8 h). 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 mu M; LNC: 2.6-8.9 mu M, F98: etoposide: 46.5 mu M; LNC: 1.4-14.7 mu M, 9L: etoposide: 58.2 mu M; LNC: 4.4-12.7 mu M). This effect was found to be particle size dependent within a range of an 8- (C6) to 33-fold (1798) 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. (c) 2006 Elsevier B.V. All rights reserved.