Jiang Yan, Wang Xiuzhen, Liu Xin, Lv Wei, Zhang Hongjuan, Zhang Mingwan, Li Xinrui, Xin Hongliang, Xu Qunwei
Department of Pharmaceutics, School of Pharmacy, and §Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University , Nanjing 211166, China.
ACS Appl Mater Interfaces. 2017 Jan 11;9(1):211-217. doi: 10.1021/acsami.6b13805. Epub 2016 Dec 23.
Glioblastoma multiforme (GBM) presents one of the most lethal brain tumor with a dismal prognosis. And nanodrug delivery system (nano-DDS) have raised a lot of concern, while the conventional nanoformulations addressed many limitations, especially the low drug loading capacity and poor stability in vivo. Herein, we proposed PTX prodrug (PTX-SS-C) conjugate self-assembled nanoparticles (PSNPs) functionalized with Pep-1, glioma homing peptide, to overcome the blood brain tumor barrier (BBTB) via interleukin 13 receptor α2 (IL-13Rα2)-mediated endocytosis for targeting GMB. This nanocarrier was with ultrahigh drug loading capacity (56.03%) and redox-sensitivity to the up-expression of glutathione in glioma tumors. And compared with PEG-PSNPs, Pep-PSNPs could significantly enhance cellular uptake in U87MG cells via IL-13Rα2-mediated endocytosis. Enhanced cytotoxicity of Pep-PSNPs against U87MG cells and BCEC cells pretreated with glutathione monoester (GSH-OEt) confirmed that this nanosystem was sensitive to reduction environment, and there was significant difference between targeting and nontargeting groups in MTT assay. Real-time fluorescence image of intracranialU87MG glioma-bearing mice revealed that Pep-PSNPs could more efficiently accumulate at tumor site and improve the penetration. Furthermore, the ex vivo fluorescence imaging and corresponding semiquantitative results displayed that the glioma fluorescence intensity of Pep-PSNPs group was 1.74-fold higher than that of nontargeting group. Pep-PSNPs exhibited remarkable antiglioblastoma efficacy with an extended median survival time. In conclusion, Pep-PSNPs had a promising perspective as a targeting drug delivery system of PTX for glioma treatment.
多形性胶质母细胞瘤（GBM）是最致命的脑肿瘤之一，预后极差。纳米药物递送系统（nano-DDS）引起了广泛关注，而传统的纳米制剂存在许多局限性，尤其是药物负载量低和体内稳定性差。在此，我们提出了用神经胶质瘤归巢肽Pep-1功能化的紫杉醇前药（PTX-SS-C）共轭自组装纳米颗粒（PSNPs），通过白细胞介素13受体α2（IL-13Rα2）介导的内吞作用克服血脑肿瘤屏障（BBTB），以靶向GBM。这种纳米载体具有超高的药物负载量（56.03%），并且对神经胶质瘤肿瘤中谷胱甘肽的高表达具有氧化还原敏感性。与聚乙二醇化PSNPs（PEG-PSNPs）相比，Pep-PSNPs可通过IL-13Rα2介导的内吞作用显著增强U87MG细胞的细胞摄取。Pep-PSNPs对经谷胱甘肽单酯（GSH-OEt）预处理的U87MG细胞和脑微血管内皮细胞（BCEC）的细胞毒性增强，证实该纳米系统对还原环境敏感，MTT试验中靶向组和非靶向组之间存在显著差异。颅内接种U87MG神经胶质瘤小鼠的实时荧光成像显示，Pep-PSNPs能够更有效地在肿瘤部位积聚并改善渗透。此外，离体荧光成像及相应的半定量结果显示，Pep-PSNPs组的神经胶质瘤荧光强度比非靶向组高1.74倍。Pep-PSNPs表现出显著的抗胶质母细胞瘤疗效，中位生存时间延长。总之，Pep-PSNPs作为一种用于神经胶质瘤治疗的紫杉醇靶向给药系统具有广阔的前景。
