Improving the therapeutic window of anticancer agents by β-cyclodextrin encapsulation: Experimental and theoretical insights

Abstract

3-Nitro-2H-chromene derivatives exhibit promising anticancer activities, but their clinical translation is hindered by poor aqueous solubility. Herein, we report a cyclodextrin complexation strategy to improve the solubility and therapeutic efficacy of 8-methoxy-2-(4-methoxy phenyl)-3-nitro-2H-chromene (MNC), a potent anticancer agent. Solid inclusion complexes of MNC: β-cyclodextrin (β-CD) were synthesized by co-precipitation and kneading methods, and comprehensively characterized using UV–vis, Fluorescence, Fourier Transform Infrared (FT-IR), Differential scanning calorimetry (DSC), X-ray diffraction (XRD), Scanning electron microscope (SEM), 1H NMR, and mass spectrometric techniques. A 1:1 host–guest stoichiometry was verified by phase solubility and UV–Vis spectroscopic studies. β-CD complexation remarkably enhanced the aqueous solubility of hydrophobic MNC. Cytotoxicity evaluation against different human cancer cell lines such as breast cancer (MCF-7, MDA-MB-231), lung cancer (A549), and liver cancer (HepG2) demonstrated superior anticancer activity of the co-precipitated MNC: β-CD complex compared to free MNC and the chemotherapeutic 5-fluorouracil. Although the host–guest interaction energy obtained from molecular docking was modest (−5.1 kcal/mol), it facilitated effective MNC encapsulation and delivery by β-CD. Density functional theory (DFT) calculations provided further insights into the inclusion phenomenon. This cyclodextrin complexation approach paves the way for developing an effective MNC formulation with improved bioavailability and anticancer therapeutic efficacy.