Albumin-targeted oxaliplatin(iv) prodrugs bearing STING agonists
- Author(s)
- Martijn Dijkstra, Michael Gutmann, Mathias Gradl, Anja Federa, Carola Jaunecker, John Vasco Breitenstein, Petra Vician, Christine Pirker, Daniel Valcanover, Petra Heffeter, Bernhard K. Keppler, Walter Berger, Christian R. Kowol
- Abstract
The anticancer platinum complex oxaliplatin exerts its activity through DNA damage and immune-stimulatory mechanisms, but is associated with adverse treatment side effects. Platinum(iv) complexes represent a promising prodrug strategy to improve tolerability and to enhance antitumor efficacy via attachment of additional bioactive ligands or tumor-targeting moieties. In the present study, oxaliplatin(iv) complexes containing immune-stimulatory STING agonists SR-717 or MSA-2 were synthesized and their biological properties were studied. Whereas the Pt-SR-717 compound was fast reduced, Pt-MSA-2 complexes displayed significantly higher reductive stability reflected by low in vitro cytotoxicity. Although the platinum(iv) complexes activated interferon regulatory factor (IRF) and NF-κB signaling pathways less effectively compared to the free STING agonists, reducing conditions elevated cytotoxicity and STING downstream signaling, particularly for MSA-2-containing prodrugs. Rapid albumin binding of a maleimide-containing Pt-MSA-2 derivative resulted in elevated plasma levels, prolonged blood circulation, and enhanced tumor accumulation of platinum in CT-26 tumor-bearing mice. The Pt-MSA-2 complexes triggered immune activation and cytokine secretion without hematotoxicity usually associated with free oxaliplatin. The albumin-targeted Pt-MSA-2 drug significantly inhibited tumor growth after intravenous application, while the non-maleimide complex was effective only when applied peritumorally. However, the effects were not enhanced compared to mono-treatment with oxaliplatin or MSA-2, indicating a lack of synergism between the two simultaneously released agents. Our results demonstrate that oxaliplatin(iv) complexes represent a valuable strategy for enhanced tumor-targeting and adverse effect reduction, but question the simultaneous release of STING agonists and free oxaliplatin as a potent strategy towards synergistic antineoplastic activity.
- Organisation(s)
- Department of Inorganic Chemistry
- External organisation(s)
- Vienna Doctoral School in Chemistry (DoSChem), Medizinische Universität Wien, Research Cluster Translational Cancer Therapy Research
- Journal
- Inorganic Chemistry Frontiers
- Volume
- 12
- Pages
- 4284-4305
- No. of pages
- 22
- ISSN
- 2052-1545
- DOI
- https://doi.org/10.1039/d5qi00433k
- Publication date
- 04-2025
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104003 Inorganic chemistry, 301904 Cancer research
- ASJC Scopus subject areas
- Inorganic Chemistry
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/ead85ce1-b775-410d-95ff-23181daf05cc