Qu Ding, Sun Wenjie, Liu Mingjian, Liu Yuping, Zhou Jing, Chen Yan
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China; Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China.
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China.
Int J Pharm. 2016 Apr 30;503(1-2):90-101. doi: 10.1016/j.ijpharm.2016.03.001. Epub 2016 Mar 4.
A hepatic tumor bitargeted microemulsions drug delivery system using coix seed oil and coix seed polysaccharide (CP) acting as anticancer components, as well as functional excipients, was developed for enhanced tumor-specific accumulation by CP-mediated enhancement on passive tumor targeting and modification of galactose stearate (tumor-targeted ligand). In the physicochemical characteristics studies, galactose stearate-modified coix seed multicomponent microemulsions containing 30% CP (w%) (Gal-C-MEs) had a well-defined spherical shape with a small size (47.63 ± 1.41 nm), a narrow polydispersity index (PDI, 0.101 ± 0.002), and a nearly neutral surface charge (-4.37 ± 1.76 mV). The half-maximal inhibitory concentration (IC50) of Gal-C-MEs against HepG2 cells was 70.2 μg/mL, which decreased by 1.8-fold in comparison with that of coix seed multicomponent microemulsions (C-MEs). The fluorescence intensity of fluorescein isothiocyanate (FITC)-loaded Gal-C-MEs (FITC-Gal-C-MEs) internalized by HepG2 cells was 1.8-fold higher than that of FITC-loaded C-MEs (FIT C-C-MEs), but the cellular uptake of the latter became reduce by 1.6-fold when the weight ratio of CP decreased up to 10%. In the cell apoptosis studies, C-MEs (containing 30% CP) did not show a significant difference with Gal-C-MEs, but exhibited 3.3-fold and 1.5-fold increase relative to C-MEs containing 10% CP and 20% CP, respectively. In the in vivo tumor targeting studies, Cy5-loaded Gal-C-MEs (Cy5-Gal-C-MEs), notably distributed in the tumor sites and still found even at 48 h post-administration, displayed the strongest capability of tumor tissue accumulation and retention among all the test groups. Most importantly, Gal-C-MEs had stronger inhibition of tumor growth, prolonged survival time and more effectively tumor cell apoptosis induction in comparison with C-MEs containing different amounts of CP, which further confirmed that a certain amount of CP and tumor-targeted ligand were of great importance to potent anticancer efficacy. The aforementioned results suggested that Gal-C-MEs presented promising potential as a highly effective and safe anticancer drug delivery system for enhanced liver cancer delivery.
开发了一种肝肿瘤双靶向微乳给药系统，该系统使用薏苡仁油和薏苡仁多糖（CP）作为抗癌成分以及功能性辅料，通过CP介导增强被动肿瘤靶向作用和修饰硬脂酸半乳糖（肿瘤靶向配体）来增强肿瘤特异性蓄积。在物理化学特性研究中，含有30% CP（w%）的硬脂酸半乳糖修饰的薏苡仁多组分微乳（Gal-C-MEs）具有明确的球形形状，粒径小（47.63±1.41 nm），多分散指数窄（PDI，0.101±0.002），表面电荷接近中性（-4.37±1.76 mV）。Gal-C-MEs对HepG2细胞的半数抑制浓度（IC50）为70.2 μg/mL，与薏苡仁多组分微乳（C-MEs）相比降低了1.8倍。异硫氰酸荧光素（FITC）标记的Gal-C-MEs（FITC-Gal-C-MEs）被HepG2细胞内化后的荧光强度比FITC标记的C-MEs（FITC-C-MEs）高1.8倍，但当CP重量比降至10%时，后者的细胞摄取量降低了1.6倍。在细胞凋亡研究中，C-MEs（含30% CP）与Gal-C-MEs相比无显著差异，但相对于含10% CP和20% CP的C-MEs，分别增加了3.3倍和1.5倍。在体内肿瘤靶向研究中，Cy5标记的Gal-C-MEs（Cy5-Gal-C-MEs）显著分布于肿瘤部位，甚至在给药后48小时仍可检测到，在所有测试组中显示出最强的肿瘤组织蓄积和滞留能力。最重要的是，与含不同量CP的C-MEs相比，Gal-C-MEs对肿瘤生长的抑制作用更强，延长了生存时间，并更有效地诱导肿瘤细胞凋亡，这进一步证实了一定量CP和肿瘤靶向配体对有效抗癌疗效至关重要。上述结果表明，Gal-C-MEs作为一种高效、安全的抗癌药物递送系统，在增强肝癌递送方面具有广阔的应用前景。
