ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2026
Improved Systemic Immunochemotherapy Employing an Oxaliplatin-TLR7/8 Agonist Prodrug Strategy.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Systemic application of Toll-like receptor 7/8 (TLR7/8) agonists against cancer is severely limited due to uncontrolled immune activation. In this study, a platinum(IV)-based prodrug strategy is developed for the systemic administration of a TLR7/8 agonist, selectively activated in the malignant tissue simultaneously with the immunogenic cell death inducer oxaliplatin. Two oxaliplatin(IV)-based complexes are synthesized comprising the TLR7/8 agonist gardiquimod: Ox-Gardi-PEG, containing polyethylene glycol as the second axial ligand, and Ox-Gardi-Mal, a maleimide-bearing derivative to exploit the tumor-targeting effects of serum albumin. In vitro, cytotoxicity and immune pathway-inducing potency of Ox-Gardi-PEG and Ox-Gardi-Mal are diminished under standard cell culture conditions compared to free oxaliplatin and gardiquimod, respectively, and markedly enhanced under reducing conditions, underscoring the activation-by-reduction concept. In vivo, Ox-Gardi-Mal shows superior and TLR7/8 signaling-dependent anticancer efficacy and prolongs overall survival of cancer-bearing mice, while mitigating hematotoxic effects associated with oxaliplatin. Therapy significantly elevates expression of MHC-I on antigen-presenting immune cell subsets, increases the frequency of activated plasmacytoid dendritic cells and tumor-infiltrating CD8
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