title: Ursolic acid incorporation does not prevent the formation of a non-lamellar phase in pH-sensitive and long-circulating liposomes.
abstract: Ursolic acid (UA) is a triterpene found in different plant species that has been shown to possess significant antitumor activity. However, UA presents a low water solubility, which limits its biological applications. In this context, our research group has proposed the incorporation of UA in long-circulating and pH-sensitive liposomes (SpHL-UA).These liposomes, composed of dioleylphosphatidylethanolamine (DOPE), cholesteryl hemisuccinate (CHEMS), and distearoylphosphatidylethanolamine-polyethylene glycol2000 (DSPE-PEG2000), were shown to be very promising carriers for UA. Considering that the release of UA from SpHL-UA and its antitumor activity depend upon the occurrence of the lamellar to non-lamellar phase transition of DOPE, in the present work, the interactions of UA with the components of the liposomes were evaluated, aiming to clarify their role in the structural organization of DOPE. The study was carried out by differential scanning calorimetry (DSC) and small-angle X-ray scattering (SAXS) under low hydration conditions. DSC studies revealed that DOPE phase transition temperatures did not shift significantly upon UA addition. On the other hand, in SAXS studies, a different pattern of DOPE phase organization was observed in the presence of UA, with the occurrence of the cubic phase Im3m at 20 °C and the cubic phase Pn3m at 60 °C. These findings suggest that UA interacts with the lipids and changes their self-assembly. However, these interactions between the lipids and UA were unable to eliminate the lamellar to non-lamellar phase transition, which is essential for the cytoplasmic delivery of UA molecules from SpHL-UA.
authors.affiliation: Faculty of Pharmacy, and ‡Physics Department, Institute of Exact Sciences, Universidade Federal de Minas Gerais , Belo Horizonte, Minas Gerais 31270-901, Brazil.
authors.forename: Sávia C A
authors.initials: SC
authors.lastname: Lopes
authors.forename: Marcus V M
authors.initials: MV
authors.lastname: Novais
authors.forename: Diêgo S
authors.initials: DS
authors.lastname: Ferreira
authors.forename: Fernão C
authors.initials: FC
authors.lastname: Braga
authors.forename: Rogério
authors.initials: R
authors.lastname: Magalhães-Paniago
authors.forename: Ângelo
authors.initials: Â
authors.lastname: Malachias
authors.forename: Mônica C
authors.initials: MC
authors.lastname: Oliveira
mesh_terms: D002021:Buffers; D002788:Cholesterol Esters / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D044367:Phase Transition; D010710:Phosphates / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D014315:Triterpenes / Q000737:chemistry*; D000097245:Ursolic Acid
chemical_list: D002021:Buffers; D002788:Cholesterol Esters; D008081:Liposomes; D010710:Phosphates; D010714:Phosphatidylethanolamines; D011092:Polyethylene Glycols; D014315:Triterpenes; D000097245:Ursolic Acid; C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; C038089:1,2-distearoylphosphatidylethanolamine; C013440:cholesteryl succinate