L-Carnitine-conjugated nanoparticles to promote permeation across blood-brain barrier and to target glioma cells for drug delivery via the novel organic cation/carnitine transporter OCTN2
L-Carnitine-conjugated nanoparticles to promote permeation across blood-brain barrier and to target glioma cells for drug delivery via the novel organic cation/carnitine transporter OCTN2
复制标题
左旋肉碱缀合纳米粒子可促进穿过血脑屏障的渗透，并通过新型有机阳离子/肉碱转运蛋白 OCTN2 靶向神经胶质瘤细胞进行药物输送
DOI：
10.1080/21691401.2017.1384385
复制
发表时间：
2018-01-01
影响因子：
5.8
通讯作者：
Sun, Jin
中科院分区：
文献类型：
--
作者：
Kou, Longfa;Hou, Yanxian;Sun, Jin
克服血脑屏障和靶向治疗是脑胶质瘤化疗的两个关键步骤。通过利用脑毛细血管内皮细胞和胶质瘤细胞上特异性表达的Na+偶联肉毒碱转运蛋白2（OCTN 2），制备L-肉毒碱缀合的聚（乳酸-共-乙醇酸）纳米粒（LC-PLGA NPs），以实现增强的BBB渗透和胶质瘤细胞靶向。L-肉毒碱的缀合物显著增强了PLGA纳米颗粒在BBB内皮细胞系hCMEC/D3和胶质瘤细胞系T98 G中的摄取。摄取依赖于Na+，并被过量的游离L-肉碱抑制，表明OCTN 2参与了该过程。体内小鼠研究表明，LC-PLGA NP导致脑中的高积累，如生物分布和成像测定所示。此外，与紫杉醇和紫杉醇负载的未修饰的PLGA NP相比，药物负载的LC-PLGA NP在2D-细胞和3D-球体模型中均显示出改善的抗胶质瘤功效。优化了与纳米颗粒连接的配体的PEG间隔基长度，并且具有PEG 1000（LC-1000-PLGA NPs）的制剂显示出最大的靶向效率。我们的结论是，L-肉毒碱介导的细胞识别和内化通过OCTN 2显着促进跨血脑屏障的纳米颗粒的转胞吞和神经胶质瘤细胞中的纳米颗粒的摄取，从而提高抗胶质瘤的疗效。[图片]
Overcoming blood-brain barrier (BBB) and targeting tumor cells are two key steps for glioma chemotherapy. By taking advantage of the specific expression of Na+-coupled carnitine transporter 2 (OCTN2) on both brain capillary endothelial cells and glioma cells, L-carnitine conjugated poly(lactic-co-glycolic acid) nanoparticles (LC-PLGA NPs) were prepared to enable enhanced BBB permeation and glioma-cell targeting. Conjugation of L-carnitine significantly enhanced the uptake of PLGA nanoparticles in the BBB endothelial cell line hCMEC/D3 and the glioma cell line T98G. The uptake was dependent on Na+ and inhibited by the excessive free L-carnitine, suggesting involvement of OCTN2 in the process. In vivo mouse studies showed that LC-PLGA NPs resulted in high accumulation in the brain as indicated by the biodistribution and imaging assays. Furthermore, compared to Taxol and paclitaxel-loaded unmodified PLGA NPs, the drug-loaded LC-PLGA NPs showed improved anti-glioma efficacy in both 2D-cell and 3D-spheroid models. The PEG spacer length of the ligand attached to the nanoparticles was optimized, and the formulation with PEG1000 (LC-1000-PLGA NPs) showed the maximum targeting efficiency. We conclude that L-carnitine-mediated cellular recognition and internalization via OCTN2 significantly facilitate the transcytosis of nanoparticles across BBB and the uptake of nanoparticles in glioma cells, resulting in improved anti-glioma efficacy.[GRAPHICS]