AT101-Loaded Cubosomes as an Alternative for Improved Glioblastoma Therapy.
AT101-Loaded Cubosomes as an Alternative for Improved Glioblastoma Therapy.
复制标题
DOI：
10.2147/ijn.s265061
复制
发表时间：
2020
影响因子：
8
通讯作者：
Held-Feindt J
中科院分区：
文献类型：
--
作者：
Flak DK;Adamski V;Nowaczyk G;Szutkowski K;Synowitz M;Jurga S;Held-Feindt J
AT101是棉籽衍生的多酚棉酚的R-（-）-对映体，由于其能够触发自噬细胞死亡以及促进肿瘤细胞凋亡，因此在多形性胶质母细胞瘤（GBM）治疗中是一种有前途的药物。它确实有一些局限性，如在水基介质中的溶解度差，因此生物利用度低，这影响了它在治疗过程中的反应率。为了克服这一缺点并提高AT 101的抗癌潜力，已经提出使用基于立方体的制剂用于AT 101药物递送。这是第一次报告使用立方体作为AT 101药物载体在GBM细胞。使用自上而下的方法，从单油酸甘油酯（GMO）和表面活性剂Pluronic F-127制备负载有AT 101的立方体。在分散之前将药物引入脂质中。然后对制备的制剂进行复杂的物理化学和生物学表征。AT101-cubosomes的制剂是高度稳定的胶体，具有高的药物包封率（97.7%）和连续的，持续的药物释放超过72小时接近35%。使用选择性和灵敏的NMR扩散法，药物被证明是有效地结合到基于脂质的立方体。体外成像研究表明，立方纳米颗粒摄取到GBM细胞的高效率，以及它们渗透到肿瘤球体的显著能力。用AT101-负载的立方体处理GBM细胞，而不是用游离药物，诱导细胞骨架重排和肌动蛋白纤维缩短。所制备的纳米颗粒显示出对GBM细胞（A172和LN 229细胞系）比对正常脑细胞（SVGA和HMC 3细胞系）更强的体外细胞毒性作用。结果表明，GMO-AT101立方体制剂是GBM治疗的替代方法的有前途的基本工具。
AT101, the R-(-)-enantiomer of the cottonseed-derived polyphenol gossypol, is a promising drug in glioblastoma multiforme (GBM) therapy due to its ability to trigger autophagic cell death but also to facilitate apoptosis in tumor cells. It does have some limitations such as poor solubility in water-based media and consequent low bioavailability, which affect its response rate during treatment. To overcome this drawback and to improve the anti-cancer potential of AT101, the use of cubosome-based formulation for AT101 drug delivery has been proposed. This is the first report on the use of cubosomes as AT101 drug carriers in GBM cells. Cubosomes loaded with AT101 were prepared from glyceryl monooleate (GMO) and the surfactant Pluronic F-127 using the top–down approach. The drug was introduced into the lipid prior to dispersion. Prepared formulations were then subjected to complex physicochemical and biological characterization. Formulations of AT101-loaded cubosomes were highly stable colloids with a high drug entrapment efficiency (97.7%) and a continuous, sustained drug release approaching 35% over 72 h. Using selective and sensitive NMR diffusometry, the drug was shown to be efficiently bound to the lipid-based cubosomes. In vitro imaging studies showed the high efficiency of cubosomal nanoparticles uptake into GBM cells, as well as their marked ability to penetrate into tumor spheroids. Treatment of GBM cells with the AT101-loaded cubosomes, but not with the free drug, induced cytoskeletal rearrangement and shortening of actin fibers. The prepared nanoparticles revealed stronger in vitro cytotoxic effects against GBM cells (A172 and LN229 cell lines), than against normal brain cells (SVGA and HMC3 cell lines). The results indicate that GMO-AT101 cubosome formulations are a promising basic tool for alternative approaches to GBM treatment.