Improvement of ursolic and oleanolic acids’ antitumor activity by complexation with hydrophilic cyclodextrins

• Published in: Biomedicine & pharmacotherapy 2016-10, Vol.83, p.1095-1104
• Main Authors: Oprean, Camelia, Mioc, Marius, Csányi, Erzsébet, Ambrus, Rita, Bojin, Florina, Tatu, Calin, Cristea, Mirabela, Ivan, Alexandra, Danciu, Corina, Dehelean, Cristina, Paunescu, Virgil, Soica, Codruta
• Format: Article
• Language: English
• Subjects: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Anti-proliferative; Antineoplastic Agents - pharmacology; beta-Cyclodextrins - pharmacology; Calorimetry, Differential Scanning; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Evaluation, Preclinical; gamma-Cyclodextrins - pharmacology; Hydrophilic cyclodextrins; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; Internal Medicine; Medical Education; Melanoma; Mice; Molecular Docking Simulation; Oleanolic acid; Oleanolic Acid - chemistry; Oleanolic Acid - pharmacology; Triterpenes - chemistry; Triterpenes - pharmacology; Ursolic Acid; X-Ray Diffraction
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2016.08.030

Abstract Ursolic and oleanolic acids have been brought into the spotlight of research due to their chemopreventive, anti-inflammatory and immunomodulatory properties. The most important disadvantage of ursolic and oleanolic acids is their weak water solubility which limits their bioavailability. Pentacyclic triterpenes can form inclusion complexes with different types of cyclodextrins which provide the hydrophilic matrix requested for the molecular dispersion of drugs in order to become more water soluble. The aim of the current study is the complexation of ursolic and oleanolic acids with hydrophilic cyclodextrins in order to achieve an improvement of their pharmacological effect. After the virtual screening of the binding affinities between ursolic and oleanolic acids and various cyclodextrins, 2-hydroxypropyl-β-cyclodextrin and 2-hydroxypropil-γ-cyclodextrin were selected as host-molecules for the inclusion complexation. Using the scanning electron microscopy, differential scanning calorimetry and X-ray diffraction the formation of real inclusion complexes between ursolic and oleanolic acids and the two cyclodextrins was confirmed. The anti-proliferative potential of the complexes was tested in vitro on several melanoma cell lines, using the pure compounds as reference. The complexes exhibited higher in vitro anti-proliferative activity as compared to the pure compounds; this improvement was significant for ursolic acid complexes, the highest activity being reported for the 2-hydroxypropil-γ-cyclodextrin complex. Weaker results were recorded for the oleanolic acid complexes where 2-hydroxypropyl-β-cyclodextrin proved to be the most fitted inclusion partner. The entrapment of the two active compounds inside ramified hydrophilic cyclodextrins proved to be a suitable option to increase their anti-proliferative activity.