Albumin-targeting of an oxaliplatin-releasing platinum(iv) prodrug results in pronounced anticancer activity due to endocytotic drug uptake in vivo
- Author(s)
- Hemma Schueffl, Sarah Theiner, Gerrit Hermann, Josef Mayr, Philipp Fronik, Diana Groza, Sushilla van Schonhooven, Luis Galvez, Nadine S. Sommerfeld, Arno Schintlmeister, Siegfried Reipert, Michael Wagner, Robert M. Mader, Gunda Koellensperger, Bernhard K. Keppler, Walter Berger, Christian R. Kowol, Anton Legin, Petra Heffeter
- Abstract
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 in vivo 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 via 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 in vivo 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.
- Organisation(s)
- Department of Analytical Chemistry, Department of Inorganic Chemistry, Large-Instrument Facility for Environmental and Isotope Mass Spectrometry, Department of Microbiology and Ecosystem Science, Mass Spectrometry Centre
- External organisation(s)
- Medizinische Universität Wien
- Journal
- Chemical Science
- Volume
- 12
- Pages
- 12587-12599
- No. of pages
- 13
- ISSN
- 2041-6520
- DOI
- https://doi.org/10.1039/D1SC03311E
- Publication date
- 10-2021
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104003 Inorganic chemistry, 301904 Cancer research
- Keywords
- ASJC Scopus subject areas
- General Chemistry
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/72f4d99c-ade9-4fb9-b813-268295375bf6