Kratz Felix, Müller Ivonne A, Ryppa Claudia, Warnecke André
Macromolecular Prodrugs, Tumor Biology Center, Breisacher Strasse 117, 79106 Freiburg, Germany.
ChemMedChem. 2008 Jan;3(1):20-53. doi: 10.1002/cmdc.200700159.
The majority of clinically approved anticancer drugs are characterized by a narrow therapeutic window that results mainly from a high systemic toxicity of the drugs in combination with an evident lack of tumor selectivity. Besides the development of suitable galenic formulations such as liposomes or micelles, several promising prodrug approaches have been followed in the last decades with the aim of improving chemotherapy. In this review we elucidate the two main concepts that underlie the design of most anticancer prodrugs: drug targeting and controlled release of the drug at the tumor site. Consequently, active and passive targeting using tumor-specific ligands or macromolecular carriers are discussed as well as release strategies that are based on tumor-specific characteristics such as low pH or the expression of tumor-associated enzymes. Furthermore, other strategies such as ADEPT (antibody-directed enzyme prodrug therapy) and the design of self-eliminating structures are introduced. Chemical realization of prodrug approaches is illustrated by drug candidates that have or may have clinical importance.
大多数临床批准的抗癌药物的特点是治疗窗口狭窄，这主要是由于药物的高全身毒性以及明显缺乏肿瘤选择性所致。除了开发合适的药剂学制剂（如脂质体或胶束）外，在过去几十年中还采用了几种有前景的前药方法，旨在改善化疗效果。在本综述中，我们阐明了大多数抗癌前药设计所依据的两个主要概念：药物靶向和药物在肿瘤部位的控释。因此，讨论了使用肿瘤特异性配体或大分子载体的主动和被动靶向，以及基于肿瘤特异性特征（如低pH值或肿瘤相关酶的表达）的释放策略。此外，还介绍了其他策略，如抗体导向酶前药疗法（ADEPT）和自消除结构的设计。具有或可能具有临床重要性的候选药物说明了前药方法的化学实现。
