Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, and State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.
College of Medicine, Nankai University, Tianjin 300071, China.
Mol Pharm. 2020 Jun 1;17(6):2072-2082. doi: 10.1021/acs.molpharmaceut.0c00232. Epub 2020 May 11.
Reports on the comprehensive factors for design considerations of hypoxia-activated prodrugs (HAPs) are rare. We introduced a new model system composed of a series of highly water-soluble HAPs, providing a platform to comprehensively understand the interaction between HAPs and hypoxic biosystems. Specifically, four kinds of new HAPs were designed and synthesized, containing the same biologically active moiety but masked by different bioreductive groups. Our results demonstrated that the activity of the prodrugs was strongly dependent on not only the molecular structure but also the hypoxic tumor microenvironment. We found the presence of a direct linear relationship between cytotoxicity of the HAPs and the reduction potential of whole molecule/oxygen concentration/reductase expression. Moreover, limited blood vasculature in hypoxic regions was also a critical barrier for effective activation of the HAPs. This study offers a comprehensive insight into understanding the design factors required for HAPs.
关于缺氧激活前药（HAPs）设计考虑因素的综合报告很少。我们引入了一个由一系列高水溶性 HAPs 组成的新模型系统，为全面了解 HAPs 与缺氧生物系统之间的相互作用提供了一个平台。具体来说，设计并合成了四种新型 HAPs，它们含有相同的生物活性部分，但被不同的生物还原基团掩蔽。我们的结果表明，前药的活性不仅强烈依赖于分子结构，还依赖于缺氧肿瘤微环境。我们发现 HAPs 的细胞毒性与整个分子/氧浓度/还原酶表达的还原电位之间存在直接的线性关系。此外，缺氧区域有限的血管系统也是有效激活 HAPs 的一个关键障碍。这项研究为理解 HAPs 所需的设计因素提供了全面的认识。
