Lv Lingyan, Jiang Yan, Liu Xin, Wang Baoyan, Lv Wei, Zhao Yue, Shi Huihui, Hu Quanyin, Xin Hongliang, Xu Qunwei, Gu Zhen
Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University , Nanjing 211166, China.
Department of Pharmacy, Zhangjiagang Hospital of Traditional Chinese Medicine, Affiliated Nanjing University of Chinese Medicine , Zhangjiagang 215600, China.
Mol Pharm. 2016 Oct 3;13(10):3506-3517. doi: 10.1021/acs.molpharmaceut.6b00523. Epub 2016 Sep 16.
Combining treatment of anticancer cells and antiangiogenesis is considered to be a potential targeted strategy for brain glioblastoma therapy. In this study, by utilizing the overexpression of Interleukin 13 receptor α2 (IL-13Rα2) on the glioma cells and heparan sulfate on neovascular endothelial cells, we developed a paclitaxel (PTX) loaded Pep-1 and CGKRK peptide-modified PEG-PLGA nanoparticle (PC-NP-PTX) for glioma cells and neovasculature dual-targeted chemotherapy to enhance the antiglioma efficacy. There were significant differences both on the enhancement of cellular uptake in HUVEC and C6 cells and on the improvement of in vitro antiglioma activity in the respect of proliferation, tumor spheroid growth, tube formation, and migration between PC-NP-PTX and Taxol and NP-PTX. As for C6 cells, the IC were 3.59 ± 0.056, 2.37 ± 0.044, 1.38 ± 0.028, 1.82 ± 0.035, and 1.00 ± 0.016 μg/mL of Taxol, NP-PTX, Pep-NP-PTX, CGKRK-NP-PTX, and PC-NP-PTX, and for HUVEC cells, the IC were 0.44 ± 0.006, 0.33 ± 0.005, 0.25 ± 0.005, 0.19 ± 0.004, and 0.16 ± 0.004 μg/mL of Taxol, NP-PTX, Pep-NP-PTX, CGKRK-NP-PTX, and PC-NP-PTX, respectively. In vivo distribution assays confirmed that PC-NP-PTX targeted and accumulated effectively at glioma site. PC-NP-PTX showed a longer median survival time of 61 days when compared with Taxol (22 days), NP-PTX (24 days), Pep-NP-PTX (32 days), and CGKRK-NP-PTX (34 days). The in vivo antiglioma efficacy and safety evaluation showed PC-NP-PTX significantly enhanced the antiglioma efficacy and displayed negligible acute toxicity.
联合抗癌细胞和抗血管生成治疗被认为是脑胶质母细胞瘤治疗的一种潜在靶向策略。在本研究中，利用胶质瘤细胞上白细胞介素13受体α2（IL-13Rα2）的过表达和新生血管内皮细胞上硫酸乙酰肝素，我们开发了一种负载紫杉醇（PTX）的Pep-1和CGKRK肽修饰的聚乙二醇-聚乳酸纳米粒（PC-NP-PTX），用于胶质瘤细胞和新血管双重靶向化疗，以提高抗胶质瘤疗效。在人脐静脉内皮细胞（HUVEC）和C6细胞中，PC-NP-PTX在细胞摄取增强方面，以及在增殖、肿瘤球生长、管形成和迁移方面的体外抗胶质瘤活性改善方面，与紫杉醇和NP-PTX相比均存在显著差异。对于C6细胞，紫杉醇、NP-PTX、Pep-NP-PTX、CGKRK-NP-PTX和PC-NP-PTX的半数抑制浓度（IC）分别为3.59±0.056、2.37±0.044、1.38±0.028、1.82±0.035和1.00±0.016μg/mL；对于HUVEC细胞，紫杉醇、NP-PTX、Pep-NP-PTX、CGKRK-NP-PTX和PC-NP-PTX的IC分别为0.44±0.006、0.33±0.005、0.25±0.005、0.19±0.004和0.16±0.004μg/mL。体内分布试验证实PC-NP-PTX能有效地靶向并积聚在胶质瘤部位。与紫杉醇（22天）、NP-PTX（24天）、Pep-NP-PTX（32天）和CGKRK-NP-PTX（34天）相比，PC-NP-PTX的中位生存时间更长，为61天。体内抗胶质瘤疗效和安全性评价表明，PC-NP-PTX显著提高了抗胶质瘤疗效，且急性毒性可忽略不计。
