Liu Chang, Yao Sen, Li Xuqian, Wang Feng, Jiang Yanyan
a Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Department of pharmaceutics , School of Pharmacy, Fudan University , Shanghai , China.
J Drug Target. 2017 Mar;25(3):235-246. doi: 10.1080/1061186X.2016.1238091. Epub 2016 Oct 6.
iRGD (internalizing RGD) with high affinity to αν integrins was reported to enhance tumor penetrability by binding to neuropilin-1 (NRP-1). Based on our previous study, chitosan surface-modified poly (lactide-co-glycolides) nanoparticles (PLGA/CS NPs), loaded with carmustine (BCNU) and its sensitizer (O-benzylguanine, BG) showed stronger anti-tumor effect than free drugs. In present study, PLGA/CS NPs (NPs) with core-shell structure were prepared and modified with iRGD or mPEG. F98, C6 or U87 cell lines with different receptors levels were selected for in vitro and in vivo studies. After administration of iRGD-mediated NPs, including iRGD-modified NPs (iRGD-NPs) and co-administration of iRGD and NPs (iRGD + NPs), their effects on glioma were compared with NPs. iRGD-NPs showed stronger cytotoxicity and cellular uptake than other groups. iRGD-NPs and iRGD + NPs displayed deeper tumor penetration and stronger anti-invasion effect on three dimensional (3D) glioma spheroids than NPs. On F98 glioma-bearing mice model, iRGD-mediated NPs showed enhanced crossing BBB ability and brain tumor accumulation levels. Correspondingly, the median survival time of iRGD + NPs, iRGD-NPs and NPs groups were 58, 49 and 34.5 days, respectively. Present studies supported the iRGD-mediated strategy to improve the efficacy of antitumor drug delivery system. Importantly, co-administration of iRGD may be a greater way over the conjugation of iRGD.
据报道，对αν整合素有高亲和力的iRGD（内化RGD）通过与神经纤毛蛋白-1（NRP-1）结合来增强肿瘤穿透性。基于我们之前的研究，负载卡莫司汀（BCNU）及其敏化剂（O-苄基鸟嘌呤，BG）的壳聚糖表面修饰聚（丙交酯-共-乙交酯）纳米颗粒（PLGA/CS NPs）显示出比游离药物更强的抗肿瘤作用。在本研究中，制备了具有核壳结构的PLGA/CS NPs并用iRGD或甲氧基聚乙二醇（mPEG）进行修饰。选择具有不同受体水平的F98、C6或U87细胞系进行体外和体内研究。给予iRGD介导的纳米颗粒后，包括iRGD修饰的纳米颗粒（iRGD-NPs）以及iRGD与纳米颗粒联合给药（iRGD + NPs），将它们对胶质瘤的作用与纳米颗粒进行比较。iRGD-NPs比其他组显示出更强的细胞毒性和细胞摄取。iRGD-NPs和iRGD + NPs对三维（3D）胶质瘤球体显示出比纳米颗粒更深的肿瘤穿透和更强的抗侵袭作用。在F98荷胶质瘤小鼠模型上，iRGD介导的纳米颗粒显示出增强的穿越血脑屏障能力和脑肿瘤蓄积水平。相应地，iRGD + NPs、iRGD-NPs和纳米颗粒组的中位生存时间分别为58天、49天和34.5天。目前的研究支持iRGD介导的策略可提高抗肿瘤药物递送系统的疗效。重要的是，iRGD联合给药可能比iRGD偶联是更好的方式。
