Hu Zhiyuan, Luo Fang, Pan Yifeng, Hou Can, Ren Lifeng, Chen Jiji, Wang Jiwei, Zhang Yangde
Department of Biomedical Engineering, Xiangya Hospital, Central South University, Changsha 410008, China.
J Biomed Mater Res A. 2008 Jun 1;85(3):797-807. doi: 10.1002/jbm.a.31615.
In this study, a new poly(lactic acid)-poly (ethylene oxide)-Arg-Gly-Asp (PLA-PEO-RGD) derivative was synthesized, and paclitaxel-loaded PLA-PEO-RGD micelles were prepared by this derivative. The solubility assay showed that micelles mixed with Pluronic F-68 as surfactant could increase the solubility of this hydrophobic paclitaxel in aqueous solution. The cell-binding assay showed that PLA-PEO-RGD micelle (IC(50) = 11.13 +/- 1.38 nmol/L) had about 3.6-fold higher integrin avidity than PLA-PEO-RGD conjugates (IC(50) = 40.33 +/- 3.12 nmol/L). The avidity of micelle was also higher than RGD4C peptide (IC(50) = 24.44 +/- 1.21 nmol/L). The in vitro drug release profile of drug-loaded PLA-PEO-RGD micelles exhibited initial burst release to 37% +/- 2% (w/w) during the first 12 h, and then the release rate became steady in a controlled release manner. Furthermore, treatment of the MDA-MB-435 breast cancer cell line with paclitaxel-loaded PLA-PEO-RGD micelles yielded cytotoxicities, with EC(50) values of approximately 30 mumol/L. The paclitaxel-loaded PLA-PEO-RGD micelles treated group showed the most dramatic tumor reduction in MDA-MB-435 tumor-bearing nude mice, and the final mean tumor load was 31 +/- 16 mm(3) (mean +/- SD; n = 8). (125)I-labeled micelles administration resulted in significant (p < 0.001) higher tumor uptake (2.68% +/- 0.14%, ID/g) of PLA-PEO-RGD micelles compared to PLA-PEO micelles (0.84% +/- 0.09%, ID/g) after 2.5 h postinjection. Biodistribution study showed the best blood clearance of PLA-PEO-RGD micelles after 4.5 h postinjection. The results of this study suggest that paclitaxel-loaded PLA-PEO-RGD micelles based on the specific recognition of alpha(V)beta(3) integrin represent a potential and powerful target delivery technology.
在本研究中，合成了一种新型聚乳酸-聚环氧乙烷-精氨酸-甘氨酸-天冬氨酸（PLA-PEO-RGD）衍生物，并以此衍生物制备了载紫杉醇的PLA-PEO-RGD胶束。溶解度测定表明，与作为表面活性剂的普朗尼克F-68混合的胶束可提高这种疏水性紫杉醇在水溶液中的溶解度。细胞结合试验表明，PLA-PEO-RGD胶束（IC(50)=11.13±1.38 nmol/L）的整合素亲和力比PLA-PEO-RGD缀合物（IC(50)=40.33±3.12 nmol/L）高约3.6倍。胶束的亲和力也高于RGD4C肽（IC(50)=24.44±1.21 nmol/L）。载药PLA-PEO-RGD胶束的体外药物释放曲线显示，在前12小时内初始突释至37%±2%（w/w），然后释放速率以控释方式趋于稳定。此外，用载紫杉醇的PLA-PEO-RGD胶束处理MDA-MB-435乳腺癌细胞系产生了细胞毒性，EC(50)值约为30 μmol/L。载紫杉醇的PLA-PEO-RGD胶束处理组在荷MDA-MB-435肿瘤的裸鼠中显示出最显著的肿瘤缩小，最终平均肿瘤负荷为31±16 mm(3)（平均值±标准差；n = 8）。注射(125)I标记的胶束后，与PLA-PEO胶束（0.84%±0.09%，ID/g）相比，PLA-PEO-RGD胶束在注射后2.5小时的肿瘤摄取量显著更高（2.68%±0.14%，ID/g）（p < 0.001）。生物分布研究表明，注射后4.5小时PLA-PEO-RGD胶束的血液清除效果最佳。本研究结果表明，基于α(V)β(3)整合素特异性识别的载紫杉醇PLA-PEO-RGD胶束代表了一种潜在且强大的靶向递送技术。
