Titel
Albumin-targeted oxaliplatin(iv) prodrugs bearing STING agonists
Autor*in
Michael Gutmann
Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna
Mathias Gradl
Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna
... show all
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.
Objekt-Typ
Sprache
Englisch [eng]
Persistent identifier
Erschienen in
Titel
Inorganic Chemistry Frontiers
Band
12
Ausgabe
13
ISSN
2052-1553
Erscheinungsdatum
2025
Seitenanfang
4284
Seitenende
4305
Publication
Royal Society of Chemistry (RSC)
Erscheinungsdatum
2025
Zugänglichkeit
Rechte
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