Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
Eur J Pharm Sci. 2012 Mar 12;45(4):429-35. doi: 10.1016/j.ejps.2011.08.027. Epub 2011 Sep 1.
Newly formed tumor vasculature has proven to be an effective target for tumor therapy. A strategy to attack this angiogenic tumor vasculature is to initiate local blood vessel congestion and consequently induce massive tumor cell necrosis. Vascular disrupting agents (VDAs) typically bind to tubulin and consequently disrupt microtubule dynamics. Colchicine and its derivatives (colchicinoids) are very potent tubulin binding compounds but have a narrow therapeutic index, which may be improved by employing a liposomal targeting strategy. However, as a result of their physicochemical properties, colchicinoids are problematic to retain in liposomes, as they are released relatively rapidly upon encapsulation. To overcome this limitation, two hydrolyzable PEGylated derivatives of colchicine were developed for encapsulation into the aqueous core of long-circulating liposomes: a moderately rapid hydrolyzing PEGylated colchicinoid containing a glycolic acid linker (prodrug I), and a slower hydrolyzing PEGylated colchicinoid with a lactic acid linker (prodrug II). Hydrolysis studies at 37°C and pH 7.4 showed that prodrug I possessed relatively rapid conversion characteristics (t(1/2)=5.4 h) whereas prodrug II hydrolyzed much slower (t(1/2)=217 h). Upon encapsulation into liposomes, colchicine was released rapidly, whereas both PEGylated colchicine derivatives were efficiently retained and appeared to be released only after cleavage of the PEG-linker. This study therefore demonstrates that, in contrast to colchicine, these novel PEGylated colchicine-derived prodrugs are retained within the aqueous interior after encapsulation into liposomes, and that the release of the active parent can be controlled by using different biodegradable linkers.
新形成的肿瘤血管已被证明是肿瘤治疗的有效靶点。攻击这种血管生成的肿瘤血管的策略是引发局部血管充血，从而导致大量肿瘤细胞坏死。血管破坏剂（VDAs）通常与微管蛋白结合，从而破坏微管动力学。秋水仙碱及其衍生物（秋水仙碱类）是非常有效的微管蛋白结合化合物，但治疗指数较窄，通过采用脂质体靶向策略可能会改善。然而，由于其物理化学性质，秋水仙碱类药物在脂质体中难以保留，因为它们在封装后相对较快地释放。为了克服这一限制，开发了两种可水解的聚乙二醇化秋水仙碱衍生物用于封装到长循环脂质体的水核中：含有乙二醇酸接头的中等快速水解的聚乙二醇化秋水仙碱类药物（前药 I）和含有乳酸接头的较慢水解的聚乙二醇化秋水仙碱类药物（前药 II）。在 37°C 和 pH 7.4 下进行的水解研究表明，前药 I 具有相对较快的转化特征（t(1/2)=5.4 h），而前药 II 水解速度较慢（t(1/2)=217 h）。包封到脂质体后，秋水仙碱迅速释放，而两种聚乙二醇化秋水仙碱衍生物都被有效地保留，并且似乎只有在 PEG 接头断裂后才被释放。因此，这项研究表明，与秋水仙碱不同，这些新型聚乙二醇化秋水仙碱衍生的前药在包封到脂质体后保留在水相内部，并且可以通过使用不同的可生物降解接头来控制活性母体的释放。
