Self-assembled dual-target ibuprofen-irinotecan conjugate for colorectal cancer therapy

Self-assembled nanodrug conjugates utilize both hydrophilic and hydrophobic ligands for targeted tumor delivery, reducing systemic toxicity while enhancing therapeutic efficacy. Herein, four novel nonsteroidal anti-inflammatory drug (NSAID)-irinotecan (Ir) conjugates were synthesized by forming ester bonds between hydrophobic NSAIDs and hydrophilic Ir. These amphiphilic conjugates self-assembled into carrier-free NSAID-Ir nanoparticles (NPs) in aqueous solution. Among them, Ibu-Ir NPs demonstrated superior activity against HT-29 cells (IC₅₀ = 1.15 μM), showing 5.6-fold greater potency than free Ir. Mechanistically, Ibu-Ir NPs downregulated cyclooxygenase-2 and topoisomerase I expression, enhancing Ir's therapeutic effect. In HT-29 xenograft models, Ibu-Ir NPs was able to inhibit tumor growth, although the small sample size (n = 3) carries a high risk of statistical errors. This simple yet potent strategy combines anti-inflammatory and anticancer actions, demonstrating significant potential for colorectal cancer therapy.