School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, China.
School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, China.
Eur J Med Chem. 2022 Nov 5;241:114660. doi: 10.1016/j.ejmech.2022.114660. Epub 2022 Aug 9.
CA4 is a potent microtubule polymerization inhibitor and vascular disrupting agent. However, the in vivo efficiency of CA4 is limited owing to its poor pharmacokinetics resulting from its high lipophilicity and low water solubility. To improve the water solubility, CA4 phosphate (CA4P) has been developed and shows potent antivascular and antitumor effects. CA4P had been evaluated as a vascular disrupting agent in previousc linical trials. However, it had been discontinued due to the lack of a meaningful improvement in progression-free survival and unfavorable partial response data. Codrug is a drug design approach to chemically bind two or more drugs to improve therapeutic efficiency or decrease adverse effects. This review describes the progress made over the last twenty years in developing CA4-based codrugs to improve the therapeutic profile and achieve targeted delivery to cancer tissues. It also discusses the existing problems and the developmental prospects of CA4 codrugs.
CA4 是一种有效的微管聚合抑制剂和血管破坏剂。然而，由于其高亲脂性和低水溶性，导致其药代动力学性质较差，CA4 的体内效率受到限制。为了提高水溶性，已经开发了 CA4 磷酸盐（CA4P），并显示出强大的抗血管生成和抗肿瘤作用。CA4P 曾在前瞻性临床试验中被评估为血管破坏剂。然而，由于无进展生存期和部分缓解数据无明显改善，该药物已被停用。前药是一种药物设计方法，通过化学结合两种或多种药物来提高治疗效率或降低不良反应。本综述描述了在过去二十年中，为了改善治疗效果并实现靶向递送到癌症组织，基于 CA4 的前药的发展进展。还讨论了 CA4 前药的现有问题和发展前景。
