Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Biomaterials. 2010 Aug;31(22):5855-64. doi: 10.1016/j.biomaterials.2010.03.079.
Considering the effects of conjugated linoleic acid (CLA) on anti-tumor and anti-angiogenic in brain tumor, synergistic anti-tumor activity with taxane as well as potential activity for transporting chemotherapeutic agents across the blood-brain barrier (BBB), the purpose of this study was to synthesize CLA-paclitaxel (CLA-PTX) conjugate which could reach to the brain tissue and target brain tumor. The CLA was covalently linked to PTX. The conjugate was stable in PBS and rat plasma in vitro and had no microtubule assembly activity in solution and slight effect of arresting cell cycle progression at the G(2)-M phase. The in vitro cytotoxicity of conjugate was lower than that of PTX (p < 0.05). The conjugate showed higher cellular uptake efficiency on C6 glioma cells. The entire pharmacokinetic index revealed the significant enhancement of the conjugate pharmacokinetics compared with that in PTX (p < 0.01). The conjugate, unlike PTX, could distribute in brain tissue and retained higher concentrations throughout 360 h. The anti-tumor efficacy in brain tumor-bearing rats after administering conjugate was significantly higher than that after giving Taxol (p < 0.01). In conclusion, this CLA-PTX conjugate showed great potential to become a new prodrug of PTX and the methodology can be applied to other anticancer drugs.
鉴于共轭亚油酸 (CLA) 在脑肿瘤中的抗肿瘤和抗血管生成作用，与紫杉烷具有协同抗肿瘤活性，以及有潜力将化疗药物运送到血脑屏障 (BBB) 内，本研究旨在合成 CLA-紫杉醇 (CLA-PTX) 缀合物，使其能够到达脑组织并靶向脑肿瘤。CLA 通过化学键与 PTX 相连。该缀合物在 PBS 和大鼠血浆中稳定，在溶液中无微管组装活性，对细胞周期进展到 G2-M 期仅有轻微的阻滞作用。在体外，该缀合物的细胞毒性低于 PTX（p < 0.05）。该缀合物对 C6 神经胶质瘤细胞的摄取效率更高。整个药代动力学指数显示与 PTX 相比，该缀合物的药代动力学有显著提高（p < 0.01）。与 PTX 不同，该缀合物可以分布在脑组织中，并在 360 小时内保持更高的浓度。在脑肿瘤荷瘤大鼠中，给予缀合物后的抗肿瘤疗效明显高于 Taxol（p < 0.01）。综上所述，该 CLA-PTX 缀合物具有成为 PTX 新前药的巨大潜力，并且该方法可应用于其他抗癌药物。
