Enhanced Antitumor and Antibacterial Activities of Ursolic Acid through β-Cyclodextrin Inclusion Complexation

Ursolic acid (UA) is a pentacyclic triterpenoid known for its wide range of biological activities, including anticancer and antimicrobial effects. However, its poor solubility in water limits its therapeutic potential. Therefore, this work aims to evaluate the physicochemical properties of the ursolic acid/β-cyclodextrin inclusion complex (UA/βCD IC) and investigate the enhancement of the <i>in vitro</i> antitumor and antibacterial activities of UA when complexed with βCD. Molecular docking simulation showed that the carbonyl group of UA binds to the internal cavity of βCD, forming a hydrogen bond with the glucosidic residues of βCD. FTIR analysis revealed significant changes in the absorption peaks of UA/βCD IC, indicating interaction between the compounds, such as the reduction in intensity of the C=O and ν(O-H) bands. These results were supported by thermal analysis, as the degradation temperature of UA (233°C) and βCD (294°C) was suppressed in UA/βCD IC (191°C) compared to the free components. In addition, NMR analysis revealed significant changes in the chemical shift of the H located on the anomeric carbon (C1) of the glucose units in β-CD for the IC spectra (Δδ: 0.0041 ppm) compared to βCD, which are related to perturbations in the atomic electronic density. The colloidal characterization results also showed that UA/βCD IC has more stable colloidal properties with higher zeta potential values compared to free UA. As shown by the solubility assay, the interaction between UA and βCD formed stable inclusion complexes that increased the aqueous solubility of UA by approximately 35.85% (AUC: UA = 12.72, βCD = 6.78, UA/βCD = 17.28, <i>p</i> < 0.05). Scanning electron microscopy images revealed that IC was also associated with significant changes in particle shape and size. In addition, the UA/βCD IC showed greater antitumor activity than free UA, particularly in the MDA (71.95 ± 4.88%) and MCF-7 (73.40 ± 1.55%) cell lines. It showed similar efficacy to etoposide in HL60 (86.9 ± 0.84%) and JURKAT (85.35 ± 4.03%) cells. The UA/βCD IC significantly reduced the MIC values, improving the antibacterial activity particularly against <i>E. faecalis</i> (UA MIC: 31.3 μg/mL; UA/βCD MIC: 7.8 μg/mL), followed by <i>S. aureus</i>, <i>B. cereus</i>, and <i>K. pneumoniae</i> (UA MIC: 31.3 μg/mL; UA/βCD MIC: 15.6 μg/mL). Therefore, the UA/βCD IC significantly modifies the physicochemical properties of UA, resulting in enhanced aqueous solubility and biological properties, as confirmed by the improved antitumor and antibacterial activities.