Pharmacology & Toxicology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
Department of Pharmaceutical Sciences, A.U. College Pharmaceutical Sciences, Andhra University, Visakhapatnam, India.
Eur J Pharm Biopharm. 2018 Nov;132:168-179. doi: 10.1016/j.ejpb.2018.09.012. Epub 2018 Sep 20.
Glioblastoma multiforme (GBM) is one of the most encountered gliomas of the central nervous system. The chemotherapeutic drugs used in the treatment of GBM suffer from poor blood brain barrier penetration, severe systemic toxicities and lack of specificity towards tumor cells. There is an urgent need to explore novel drug delivery systems specifically designed for targeting GBM. Solid lipid nanoparticles (SLN) are biocompatible vehicle with less toxicity issues compared to other drug delivery systems and serve the purpose of obviating the limitations posed by existing anti-cancer drugs for GBM. In this study, angiopep-2, a ligand for the lipoprotein receptor related protein 1 (LRP 1) receptor over expressed in endothelial cells of both brain and glioma, was grafted on the surface of solid lipid nanoparticles for the delivery of docetaxel. The peptide grafted nanoparticles (A-SLN) showed increased cytotoxicity, enhanced cellular internalization and prominent apoptosis than that of unconjugated nanoparticles against U87MG human glioblastoma and GL261 mouse glioma cells. A significant dual targeting effect of A-SLN (p < 0.0001) was confirmed in in-vivo studies by real time fluorescence imaging studies in glioblastoma induced C57BL/6 mice model. Pharmacokinetic and tissue distribution studies showed selective targeting with higher accumulation of A-SLN in brain compared to Taxtotere, a marketed formulation of docetaxel. After treatment with A-SLN, the mean animal survival time of the animals was significantly enhanced to 39 days from 24 days of plain docetaxel. Collectively, this study indicated that solid lipid nanoparticles decorated with angiopep-2 can be an excellent option as targeted drug delivery system for antiglioma therapy.
多形性胶质母细胞瘤（GBM）是中枢神经系统中最常见的神经胶质瘤之一。用于治疗 GBM 的化疗药物存在血脑屏障穿透性差、严重的全身毒性和缺乏对肿瘤细胞的特异性等问题。因此，迫切需要探索专门针对 GBM 的新型药物递送系统。与其他药物递送系统相比，固体脂质纳米粒（SLN）是一种生物相容性载体，毒性问题较少，可用于克服现有抗癌药物治疗 GBM 时存在的局限性。在这项研究中，载脂蛋白 E2（一种在脑和神经胶质瘤内皮细胞中过表达的脂蛋白受体相关蛋白 1（LRP 1）受体的配体）被嫁接到固体脂质纳米粒表面，用于递送达托昔康。与未缀合的纳米粒相比，肽接枝纳米粒（A-SLN）对 U87MG 人胶质母细胞瘤和 GL261 小鼠神经胶质瘤细胞表现出更高的细胞毒性、增强的细胞内化和明显的细胞凋亡作用。通过在 C57BL/6 小鼠诱导的 GBM 模型中进行实时荧光成像研究，在体内研究中证实了 A-SLN 的显著双重靶向作用（p<0.0001）。药代动力学和组织分布研究表明，与泰索帝（一种已上市的多西他赛制剂）相比，A-SLN 具有选择性靶向作用，在大脑中的积累更高。用 A-SLN 治疗后，动物的平均存活时间从单纯多西他赛的 24 天显著延长至 39 天。综上所述，这项研究表明，载脂蛋白 E2 修饰的固体脂质纳米粒可以作为针对神经胶质瘤治疗的靶向药物递送系统的一种极好选择。
