Mayr Josef, Heffeter Petra, Groza Diana, Galvez Luis, Koellensperger Gunda, Roller Alexander, Alte Beatrix, Haider Melanie, Berger Walter, Kowol Christian R, Keppler Bernhard K
University of Vienna , Institute of Inorganic Chemistry , Waehringer Strasse 42 , A-1090 , Vienna , Austria . Email:
Institute of Cancer Research and Comprehensive Cancer Center , Medical University of Vienna , Borschkegasse 8a , A-1090 , Vienna , Austria . Email:
Chem Sci. 2017 Mar 1;8(3):2241-2250. doi: 10.1039/c6sc03862j. Epub 2016 Dec 15.
The design of targeted platinum(iv) prodrugs is a very promising approach to enhance the low selectivity of platinum(ii) drugs towards cancerous tissue in order to reduce the impact on healthy tissue and, consequently, the often severe side-effects. Herein, we report a set of mono-functionalized cis- and oxaliplatin-based platinum(iv) complexes bearing a maleimide moiety, which allows selective binding to serum albumin in the bloodstream. This leads not only to a prolonged plasma half-life by avoidance of fast renal clearance, but also to preferential accumulation of the drug in the tumor tissue due to the EPR-effect. Additionally, analogous succinimide-functionalized derivatives were prepared to verify the influence of the maleimide moiety. First experiments showed that all the maleimide compounds are stable and also possess good albumin-binding properties in whole serum. Further analytical studies on samples proved the highly increased plasma half-life, as well as tumor accumulation of the maleimide-functionalized substances. antitumor experiments with CT-26-bearing mice showed that, in contrast to the cisplatin derivatives, the oxaliplatin-based complexes had exceptionally better activity than the free drug resulting in the cure of the majority of treated mice. Subsequent analysis suggested that a distinctly faster reduction as well as reduced tumor accumulation of the cisplatin derivative might explain the worse performance compared to the oxaliplatin(iv) complexes. Taken together, a novel lead platinum(iv) complex with outstanding antitumor activity is presented, which will now be further developed towards clinical phase I trials.
设计靶向铂（IV）前药是一种非常有前景的方法，可提高铂（II）药物对癌组织的低选择性，以减少对健康组织的影响，从而减少通常严重的副作用。在此，我们报告了一组带有马来酰亚胺部分的单功能化顺铂和奥沙利铂基铂（IV）配合物，该部分允许在血流中与血清白蛋白选择性结合。这不仅通过避免快速肾脏清除而延长了血浆半衰期，而且由于EPR效应使药物优先在肿瘤组织中积累。此外，制备了类似的琥珀酰亚胺功能化衍生物以验证马来酰亚胺部分的影响。初步实验表明，所有马来酰亚胺化合物都很稳定，并且在全血清中也具有良好的白蛋白结合特性。对样品的进一步分析研究证明，马来酰亚胺功能化物质的血浆半衰期大大延长，并且在肿瘤中积累。对携带CT-26的小鼠进行的抗肿瘤实验表明，与顺铂衍生物相比，基于奥沙利铂的配合物具有比游离药物更好的活性，从而治愈了大多数接受治疗的小鼠。随后的分析表明，顺铂衍生物明显更快的还原以及肿瘤积累的减少可能解释了其与奥沙利铂（IV）配合物相比表现较差的原因。综上所述，提出了一种具有出色抗肿瘤活性的新型先导铂（IV）配合物，现在将进一步开展向I期临床试验的研发。
