title: Interaction of celecoxib with membranes: the role of membrane biophysics on its therapeutic and toxic effects.
abstract: The present work provides a biophysical characterization of the interaction of celecoxib, a cyclo-oxigenase-2 selective nonsteroidal anti-inflammatory drug, with membranes using liposomes, constituted by phosphatidylcholines, as membrane model systems. In order to mimic biological conditions, the experiments were performed at physiological pH (7.4); at an acidic pH to mimic the conditions of the inflamed cells (5.0); and at different membrane physical states (gel, ripple, and fluid phase). Important information regarding the celecoxib-membrane interactions was gathered by the complementary biophysical techniques: derivative spectrophotometry was used to determine liposome/water partition coefficient of celecoxib; dynamic light scattering (DLS) measurements were performed to study the influence of celecoxib on lipid main phase transition temperature; fluorescence binding measurements were made to assess the location of celecoxib within the membrane; and small-angle and wide-angle X-ray scattering (SAXS and WAXS) were used to assess the changes in the structure and order of phosphatidylcholine bilayers caused by the presence of celecoxib. The overall results obtained indicate that celecoxib greatly interacts with membranes. Briefly, celecoxib exhibits a high liposome/water partition coefficient that is non-pH-dependent, but the location of celecoxib within the membrane is pH-dependent. In fact, celecoxib is more deeply located inside the membrane at pH 5.0, while it locates closer to the surface at pH 7.4. DLS, SAXS, and WAXS results have shown a high membrane fluidization in the presence of celecoxib, especially at pH 7.4. Overall, the current study can contribute to a biophysical characterization of the celecoxib-membrane interaction. The relevance of the gathered results will be discussed in terms of the reported celecoxib therapeutic and toxic effects.
authors.affiliation: REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Pereira-Leite
authors.forename: Cláudia
authors.initials: C
authors.lastname: Nunes
authors.forename: José L F C
authors.initials: JL
authors.lastname: Lima
authors.forename: Salette
authors.initials: S
authors.lastname: Reis
authors.forename: Marlene
authors.initials: M
authors.lastname: Lúcio
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001703:Biophysics; D000068579:Celecoxib; D002462:Cell Membrane / Q000187:drug effects*; D008051:Lipid Bilayers / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D008958:Models, Molecular; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008051:Lipid Bilayers; D008081:Liposomes; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib