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Interaction of Clonixin with EPC Liposomes Used As Membrane Models

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Interaction of Clonixin with EPC Liposomes Used As Membrane Models Interaction of Clonixin with EPC Liposomes Used as Membrane Models HELENA FERREIRA,1 MARLENE LU´ CIO,1 JOSE´ L.F.C. LIMA,1 CARLA MATOS,2 SALETTE REIS1 1REQUIMTE, Departamento de Quı´mica-Fı´sica, Faculdade de Farma´cia, Universidade do Porto, Rua Anı´bal Cunha, 164, 4050-047 Porto, Portugal 2REQUIMTE, Faculdade Cieˆncias da Sau´de, Universidade Fernando Pessoa, Rua Carlos da Maia, no. 296, 4200-150 Porto, Portugal Received 15 December 2004; revised 15 February 2005; accepted 16 February 2005 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20351 ABSTRACT: In this work, an overall analysis of clonixin interaction with liposomes was achieved using different techniques, which allowed the evaluation of the change in different membrane’s characteristics as well as the possible location of the drug in the membrane. Clonixin acidity constants were obtained and the values are 5.5 Æ 0.08 and 2.2 Æ 0.04. Clonixin partition coefficient (Kp) between liposomes and water was also determined using derivative spectrophotometry, fluorescence quenching, and zeta- potential (z-potential). These three techniques yielded similar results. z-potential measurements were performed and an increase of the membrane negative charge with an increase of drug concentration was observed. Drug location within the bilayer was performed by fluorescence quenching using a set of n-(9-anthroyloxy) fatty acid probes (n ¼ 2, 6, 9, and 12). The fluorescence intensity of all probes was quenched by the drug. This effect is more noticeable for the outer located probe, indicating that the drug is positioning in the external part of the membrane. These same probes were used for steady-state anisotropy measurements to determine the perturbation in membrane structure induced by clonixin. Clonixin increased membrane fluidity in a concentration dependent manner, with the highest perturbation occurring nearby the 2-AS probe, closely located to the bilayer surface. ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:1277–1287, 2005 Keywords: clonixin; liposomes; drug interaction; light scattering; UV/Vis spectro- scopy; fluorescence spectroscopy; partition coefficient; drug location; membrane fluidity INTRODUCTION phenomena, such as neutrophil function inhi- bition, oxidative phosphorylation inhibition in Cyclooxygenase (COX), a membrane related mitochondria, signal transduction disruption, enzyme, is the pharmacological target of non- and the consequent interference with intracel- steroidal anti-inflammatory drugs (NSAIDs), lular calcium mobilization and protein kinase C which are therefore commonly used in inflamma- activity alteration, have all been reported by tory diseases treatment. Although low doses of Klein et al.,1 as well as a membrane fluidity NSAIDs inhibit prostaglandins biosynthesis, high alteration, which has been mentioned by several concentrations interfere with processes not de- authors.2–5 Furthermore, NSAIDs have been pendent on these mediators. Membrane related shown to inhibit the cellular proliferation rate, to alter the cell cycle regulation, and to induce apoptosis in cancer cell lines, in a mechanism in- Correspondence to: Salette Reis (Telephone: þ351-222-078- dependent from prostaglandin pathways.1 966. Fax: þ351-222-004-427; E-mail: [email protected].) There is consensual evidence that the lipid Journal of Pharmaceutical Sciences, Vol. 94, 1277–1287 (2005) ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association affinity of the NSAIDs is of major significance JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 6, JUNE 2005 1277 1278 FERREIRA ET AL. for their toxic and therapeutic actions. Indeed, quenching. Using the z-potential technique, it was depending on their hydrolipophilic character, possible to evaluate the interaction of clonixin NSAIDs can be distributed between the mem- with liposomes by measuring the membrane brane and the aqueous phases. This distribution potential arising from the drug partitioning. In determines their concentration in each phase and fact, biological membranes are charged, due to thereby controls the extents of their penetration ionized components (lipids, glycolipids, glycopro- into the membrane and/or their interactions with teins), and the resulting surface potential plays a phospholipids or other membrane components, critical role in regulatory processes, membrane– such as COX enzymes, which are embedded in membrane interactions, and in their binding capa- the lipid bilayers.6 Thus, for the study of NSAIDs’ city to solutes in solution.13,14 Additionally, to action mechanisms and their side-effects, it is of electrostatic effects, which can affect the confor- great importance to investigate the interactions mation and activity of membrane and membrane- between these drugs and biomembranes. For this bound enzymes,15,16 several cell processes are also purpose, this work was performed using lipo- related to electrostatic or polarization effects on somes of egg yolk phosphatidylcholine (EPC). the cell membrane. In this context, the character- Liposomes are generally accepted to be a suitable ization of the electrostatic membrane properties model for the study of membrane structure and induced by clonixin binding is a fundamental properties, because they are surrounded by a lipid parameter, and it also allows the quantification bilayer structurally similar to the lipidic matrix of clonixin molecules in these membranes. Conse- 6,7 of the cell membranes. Additionally, because of quently, Kp values can be calculated. being constituted by natural lipids, EPC liposomes Fluorescence quenching was also used to mea- can mimic the chemical and structural anisotropic sure clonixin’s coefficient partition. The fluores- environment of cell membranes. EPC liposomes cent n-(9-anthroyloxy)-stearic acids (n-AS, n ¼ 2, also appear to mimic the interfacial character as 6, 9, and 12) are the set of probes most widely well as the ionic, H-bond, dipole–dipole, and used for obtaining information on molecular hydrophobic interactions, which may define parti- aggregates, such as liposomes and natural mem- tioning in real biomembranes.6,7 branes.17–22 For these probes, there is evidence Traditionally, the octanol–water partition coef- that the anthroyloxy fluorophores are located at ficient (Kp) has been used to measure compounds’ a graded series of depths inside a membrane, hydrophobicity, which is correlated to drug activ- depending on its substitution position (n) in the ity. The octanol–water system is a good membrane aliphatic chain.17 Therefore, these probes, due to model when polar group interactions between the their exceptional environmental sensitivity, have solute and the phospholipid bilayer are minimal or been employed to monitor the microenvironment absent. However, since octanol can only model of membranes. These appropriate measurements non-polar interactions,8 better systems are needed allow information about the local membrane for molecules which can establish electrostatic in- structure to be inferred. According to this, besides teractions with polar groups in the membrane. the determination of clonixin’s Kp, fluorescence According to this, the study of clonixin’s partition quenching provides a mean to evaluate the posi- in a liposome/buffer system has been performed. tion and orientation of the drug in the membrane There is a more satisfactory correlation between by a comparative analysis of all probe’s quenching. this parameter and its pharmacological properties Furthermore, the fluorescent probes are capable of since clonixin has proved to be able to establish sensing a ‘‘fluidity’’ gradient through the bilayer electrostatic interactions with polar groups in the leaflet and, therefore, they were used to assess the biomembranes. The drug’s Kp was evaluated by clonixin effect in the lipid membrane fluidity. This derivative spectrophotometry, a technique that was achieved using steady-state anisotropy mea- can be used when a solute’s spectral characteristic surements, since that anisotropy depends upon changes between one media to another. Deriva- the rotational motion of the fluorophore and it is tive spectrophotometry eliminates the intense sensitive to hindrance forces imposed by the background signals that arise from light scattered microenvironment, property that has been widely by lipid vesicles, and it also improves the resolu- used to estimate membrane fluidity.18 Membrane tion of overlapping signals reported by several fluidity assessment gives useful physiologic infor- 9–12 authors. Moreover, the liposome/water Kp was mation as biomembranes need to be in a fluid state also determined by other experimental techni- in order to maintain complete biological function. ques: zeta-potential (z-potential) and fluorescence Indeed, any alteration in membrane fluidity tends JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 6, JUNE 2005 INTERACTION OF CLONIXIN WITH EPC LIPOSOMES 1279 to change movement and/or orientation of pro- Fluorescence studies were carried out on a teins floating within lipid bilayer, as reported by Perkin-Elmer LS 50B steady-state fluorescence Dave and Witorsch.23 Becceria et al.3 described a spectrometer equipped with a constant-tempera- decrease in lymphocytes membrane fluidity in ture cell holder. All data were recorded at rheumatoid arthritis, and suggested membrane 25.0 Æ 0.18C in 1-cm cuvettes with excitation and fluidification as a good indicator of NSAID’s ther- emission slits between 4.0 and 9.0 nm. Excitation apeutic effects. Another important aspect in wavelength
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