Albumin-targeted oxaliplatin(<scp>iv</scp>) prodrugs bearing STING agonists
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
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.