Schueffl Hemma, Theiner Sarah, Hermann Gerrit, Mayr Josef, Fronik Philipp, Groza Diana, van Schonhooven Sushilla, Galvez Luis, Sommerfeld Nadine S, Schintlmeister Arno, Reipert Siegfried, Wagner Michael, Mader Robert M, Koellensperger Gunda, Keppler Bernhard K, Berger Walter, Kowol Christian R, Legin Anton, Heffeter Petra
Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna Borschkegasse 8a A-1090 Vienna Austria
Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna Waehringer Str. 38 A-1090 Vienna Austria.
Chem Sci. 2021 Aug 26;12(38):12587-12599. doi: 10.1039/d1sc03311e. eCollection 2021 Oct 6.
Oxaliplatin is a very potent platinum(ii) drug which is frequently used in poly-chemotherapy schemes against advanced colorectal cancer. However, its benefit is limited by severe adverse effects as well as resistance development. Based on their higher tolerability, platinum(iv) prodrugs came into focus of interest. However, comparable to their platinum(ii) counterparts they lack tumor specificity and are frequently prematurely activated in the blood circulation. With the aim to exploit the enhanced albumin consumption and accumulation in the malignant tissue, we have recently developed a new albumin-targeted prodrug, which supposed to release oxaliplatin in a highly tumor-specific manner. In more detail, we designed a platinum(iv) complex containing two maleimide moieties in the axial position (KP2156), which allows selective binding to the cysteine 34. In the present study, diverse cell biological and analytical tools such as laser ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS), isotope labeling, and nano-scale secondary ion mass spectrometry (NanoSIMS) were employed to better understand the distribution and activation process of KP2156 (in comparison to free oxaliplatin and a non-albumin-binding succinimide analogue). KP2156 forms very stable albumin adducts in the bloodstream resulting in a superior pharmacological profile, such as distinctly prolonged terminal excretion half-life and enhanced effective platinum dose (measured by ICP-MS). The albumin-bound drug is accumulating in the malignant tissue, where it enters the cancer cells clathrin- and caveolin-dependent endocytosis, and is activated by reduction to release oxaliplatin. This results in profound, long-lasting anticancer activity of KP2156 against CT26 colon cancer tumors based on cell cycle arrest and apoptotic cell death. Summarizing, albumin-binding of platinum(iv) complexes potently enhances the efficacy of oxaliplatin therapy and should be further developed towards clinical phase I trials.
奥沙利铂是一种非常有效的铂（II）类药物，常用于针对晚期结直肠癌的多药化疗方案。然而，其疗效受到严重不良反应以及耐药性发展的限制。基于其更高的耐受性，铂（IV）前药成为了研究热点。然而，与它们的铂（II）同类物类似，它们缺乏肿瘤特异性，并且经常在血液循环中过早激活。为了利用恶性组织中白蛋白消耗和积累的增加，我们最近开发了一种新的白蛋白靶向前药，它应该以高度肿瘤特异性的方式释放奥沙利铂。更详细地说，我们设计了一种在轴向位置含有两个马来酰亚胺部分的铂（IV）配合物（KP2156），它能够选择性地与半胱氨酸34结合。在本研究中，使用了多种细胞生物学和分析工具，如激光烧蚀电感耦合等离子体质谱（LA-ICP-MS）、同位素标记和纳米级二次离子质谱（NanoSIMS），以更好地了解KP2156的分布和激活过程（与游离奥沙利铂和一种非白蛋白结合的琥珀酰亚胺类似物相比）。KP2156在血液中形成非常稳定的白蛋白加合物，从而产生优异的药理学特性，如明显延长的终末排泄半衰期和增加的有效铂剂量（通过ICP-MS测量）。与白蛋白结合的药物在恶性组织中积累，在那里它通过网格蛋白和小窝蛋白依赖性内吞作用进入癌细胞，并通过还原被激活以释放奥沙利铂。这导致KP2156基于细胞周期停滞和凋亡性细胞死亡对CT26结肠癌肿瘤具有深刻、持久的抗癌活性。总之，铂（IV）配合物与白蛋白的结合有力地增强了奥沙利铂治疗的疗效，应进一步推进至临床I期试验。
