Investigation of the Effects of Nanoparticles Containing Irinotecan/TGF-ß Receptor Inhibitor in Colorectal Cancer

Colorectal cancer (CRC) treatment with Irinotecan is often limited by dose-dependent toxicity and drug delivery mediated by transforming growth factor-β (TGF-β) signaling. Targeting TGF-β signaling in combination with chemotherapeutic agents using nanoparticle-based delivery systems represents a promising strategy to enhance therapeutic efficacy while minimizing systemic toxicity. In this study, β-cyclodextrin (β-CD)-based nanoparticles were synthesized and characterized for the encapsulation and co-delivery of irinotecan and the TGF-β receptor inhibitor LY2109761. Physicochemical characterization confirmed stable nanoparticle formation with controlled drug loading and release properties. Cytotoxicity analysis demonstrated that Irinotecan-loaded nanoparticles significantly reduced viability of HCT 116 colorectal cancer cells with an IC₅₀ of 91.3 ± 0.05 µM, representing enhanced efficacy compared to free drug treatment. Importantly, combinatorial nanoparticle treatment further reduced cell viability to 43.6%, indicating improved therapeutic performance at lower drug concentrations. Fluorescence microscopy using propidium iodide staining revealed increased membrane permeability, particularly in the combination treatment group. ELISA analysis showed a moderate decrease in TGF-β secretion following inhibitor-containing nanoparticle treatment, suggesting partial modulation of tumor survival signaling pathways. In contrast, minimal cytotoxicity was observed in non-cancerous endothelial HUVEC cells, indicating a degree of selectivity toward colorectal cancer cells and suggesting favorable in vitro tolerability of the β-CD nanoparticle system. These findings suggest that β-cyclodextrin-based co-delivery of Irinotecan and LY2109761 may enhance cytotoxic activity in colorectal cancer cells and may be associated with modulation of TGF-β-related signaling. This nanotherapeutic strategy offers an approach for improving CRC treatment efficacy while enabling dose reduction and minimizing off-target toxicity, warranting further in vivo validation.