Enhanced Antiglioma Efficacy of Ultrahigh Loading Capacity Paclitaxel Prodrug Conjugate Self-Assembled Targeted Nanoparticles
Enhanced Antiglioma Efficacy of Ultrahigh Loading Capacity Paclitaxel Prodrug Conjugate Self-Assembled Targeted Nanoparticles
复制标题
超高负载能力紫杉醇前药缀合物自组装靶向纳米颗粒增强抗神经胶质瘤功效。
DOI：
10.1021/acsami.6b13805
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发表时间：
2017-01-11
影响因子：
9.5
通讯作者：
Xu, Qunwei
中科院分区：
文献类型：
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作者：
Jiang, Yan;Wang, Xiuzhen;Xu, Qunwei
多形性胶质母细胞瘤(GBM)是最致命的脑肿瘤之一，预后很差。而传统的纳米制剂存在载药量低、体内稳定性差等问题。在此，我们提出了PTX前体药物(PTX-SS-C18)与胶质瘤归巢肽PEP-1功能化的偶联自组装纳米粒(PSNPs)，通过白介素13受体α2(IL-13Rα2)介导的靶向GMB的内吞作用来克服血脑肿瘤屏障。该纳米载体具有超高的载药量(56.03%)和对胶质瘤中谷胱甘肽表达上调的氧化还原敏感性。与PEGPSNPs相比，PEP PSNPs可通过IL-13Rα2介导的内吞作用显著增强U87 MG细胞的摄取。Pep-PSNPs对U87 MG细胞和谷胱甘肽单酯(GSH-OET)处理的BCEC细胞的杀伤作用增强，证实该纳米系统对还原环境敏感，并且靶向组和非靶向组的MTT值有显著差异。脑内U87 MG胶质瘤小鼠的实时荧光图像显示，PEP-PSNPs能更有效地在肿瘤部位聚集，并改善穿透性。此外，体外荧光成像和相应的半定量结果显示，Pep-PSNPs组胶质瘤的荧光强度是非靶向组的1.74倍。PEP-PSNPs具有显著的抗胶质母细胞瘤作用，中位生存期延长。综上所述，PEP-PSNPs作为PTX靶向给药系统在脑胶质瘤治疗中具有广阔的应用前景。
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-C18) 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.