title: Improvement of ursolic and oleanolic acids' antitumor activity by complexation with hydrophilic cyclodextrins.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Victor Babeş University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timişoara 300041, Romania. Electronic address: camelia.oprean@umft.ro.
authors.forename: Camelia
authors.initials: C
authors.lastname: Oprean
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Victor Babeş University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timişoara 300041, Romania. Electronic address: marius.mioc@umft.ro.
authors.forename: Marius
authors.initials: M
authors.lastname: Mioc
authors.affiliation: Department of Pharmaceutical Technology, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary. Electronic address: csanyi@pharm.u-szeged.hu.
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Csányi
authors.affiliation: Department of Pharmaceutical Technology, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary. Electronic address: rita-techno@freemail.hu.
authors.forename: Rita
authors.initials: R
authors.lastname: Ambrus
authors.affiliation: Department of Functional Sciences, Faculty of Medicine, Victor Babeş University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timişoara 300041, Romania. Electronic address: florinabojin@umft.ro.
authors.forename: Florina
authors.initials: F
authors.lastname: Bojin
authors.affiliation: Department of Functional Sciences, Faculty of Medicine, Victor Babeş University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timişoara 300041, Romania. Electronic address: geomed88@gmail.com.
authors.forename: Calin
authors.initials: C
authors.lastname: Tatu
authors.affiliation: "Pius Brinzeu" Timişoara County Emergency Clinical Hospital, 156 Liviu Rebreanu, Timişoara 300723, Romania. Electronic address: bunceanum@yahoo.com.
authors.forename: Mirabela
authors.initials: M
authors.lastname: Cristea
authors.affiliation: Department of Functional Sciences, Faculty of Medicine, Victor Babeş University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timişoara 300041, Romania. Electronic address: ivan.alexandra@umft.ro.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Ivan
authors.affiliation: Department of Pharmacognosy, Faculty of Pharmacy, Victor Babeş University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timişoara 300041, Romania. Electronic address: corina.danciu@umft.ro.
authors.forename: Corina
authors.initials: C
authors.lastname: Danciu
authors.affiliation: Department of Toxicology, Faculty of Pharmacy, Victor Babeş University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timişoara 300041, Romania. Electronic address: cadehelean@umft.ro.
authors.forename: Cristina
authors.initials: C
authors.lastname: Dehelean
authors.affiliation: Department of Functional Sciences, Faculty of Medicine, Victor Babeş University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timişoara 300041, Romania. Electronic address: genostem@yahoo.com.
authors.forename: Virgil
authors.initials: V
authors.lastname: Paunescu
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Victor Babeş University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., Timişoara 300041, Romania. Electronic address: codrutasoica@umft.ro.
authors.forename: Codruta
authors.initials: C
authors.lastname: Soica
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002152:Calorimetry, Differential Scanning; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D051379:Mice; D062105:Molecular Docking Simulation; D009828:Oleanolic Acid / Q000737:chemistry / Q000494:pharmacology*; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D014961:X-Ray Diffraction; D047392:beta-Cyclodextrins / Q000494:pharmacology*; D047408:gamma-Cyclodextrins / Q000494:pharmacology*; D000097245:Ursolic Acid
chemical_list: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000970:Antineoplastic Agents; D009828:Oleanolic Acid; D014315:Triterpenes; D047392:beta-Cyclodextrins; D047408:gamma-Cyclodextrins; D000097245:Ursolic Acid; C479659:hydroxypropyl-gamma-cyclodextrin
keywords: Anti-proliferative; Hydrophilic cyclodextrins; Melanoma; Oleanolic acid; Ursolic acid