Greenwald R B, Gilbert C W, Pendri A, Conover C D, Xia J, Martinez A
Enzon Inc, Piscataway, New Jersey 08854-3969, USA.
J Med Chem. 1996 Jan 19;39(2):424-31. doi: 10.1021/jm950475e.
Water soluble 2'-taxol poly(ethylene glycol) (PEG) esters have been synthesized and shown to function in vitro as prodrugs. However, in vivo experiments clearly establish that in order for these prodrugs to behave in a predictable fashion, the molecular weight of PEG must be of such magnitude so as to maintain a t1/2(circulation) > t1/2(hydrolysis). When PEG derivatives of molecular weight approximately 40 kDa were employed with paclitaxel, ca. 4% by weight of paclitaxel was carried by the water soluble prodrug form, and equivalent in vivo toxicity and increased life expectancy in the P388-treated mouse was observed. An effective method for prescreening prodrugs was found to be the acute murine lethality, which reflects the equivalency of the solubilized transport form and the native drug.
水溶性2'-紫杉醇聚乙二醇（PEG）酯已被合成，并在体外显示出作为前药的功能。然而，体内实验清楚地表明，为了使这些前药以可预测的方式发挥作用，PEG的分子量必须达到这样的程度，以维持t1/2（循环）>t1/2（水解）。当使用分子量约为40 kDa的PEG衍生物与紫杉醇结合时，约4%重量的紫杉醇以水溶性前药形式携带，并且在P388处理的小鼠中观察到了等效的体内毒性和延长的预期寿命。发现一种预筛选前药的有效方法是急性小鼠致死率，它反映了溶解的转运形式和天然药物的等效性。
