Albumin-targeted oxaliplatin(IV) prodrugs bearing STING agonists

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.