Concentration-dependent differing actions of the nonsteroidal anti-inflammatory drug, celecoxib, in distearoyl phosphatidylcholine multilamellar vesicles

Abstract

The interactions of the nonsteroidal anti-inflammatory drug, celecoxib, with 1,2-distearoyl-sn-glycero-3-phosphocholine multilamellar vesicles were studied as a function of temperature and different drug concentrations, using Fourier transform infrared spectroscopy, differential scanning calorimetry, and turbidity technique at 440 nm. Our studies reveal that celecoxib lowers the main phase-transition temperature and decreases the fluidity of the membranes at all concentrations. Celecoxib induced opposing effects on molecular order at different concentrations by increasing the ordering of the system at low concentrations and disordering it at high concentrations. Further, the drug increases the number of hydrogen bonds around the carbonyl groups at low concentrations in both phases, whereas the degree of dehydration increases at high concentrations in the gel phase. An evidence of phase separation has also been clearly observed at high concentrations. Thus, depending on the concentration used, celecoxib induces significant changes in the biophysical properties of membranes that may aid in understanding its mechanism of action.

Effects of the non-steroidal anti-inflammatory drug celecoxib on cholesterol containing distearoyl phosphatidylcholine membranes

“…A decrease in the bandwidth with increasing concentrations of CLX (statistically significant at 18 mol%) in both phases can be observed. This indicates that CLX decreases the fluidity of DSPC:Chol membranes which is also consistent with our previous results of DSPC membranes without cholesterol [22].…”

“…In addition, membrane lipid order and fluidity have been reported to be important parameters for the correct functioning of ion channels [2]. The decrease in membrane fluidity in a more biologically relevant system containing cholesterol supports the hypothesis that CLX may induce changes in the activity of membrane bound enzymes through modulating physical properties of the membrane thereby contributing to its anticancer activity [22].…”

“…The frequency of these bands give information about the order/disorder state of the membrane depending on the average trans/gauche isomerization in the system, and shifts to higher wavenumbers correspond to an increase in the number of gauche conformers which implies a more disordered state [5,23]. Figure 1 displays the average frequency changes in the CH 2 antisymmetric stretching mode of DSPC:Chol MLVs (mol ratio of 3:1), in the presence and absence of 6 and 18 mol% CLX at 30 and 65 • C. These CLX concentrations were chosen according to our previous findings which indicated that 6 and 18 mol% CLX show opposing effects on DSPC model membranes [22]. As seen from the figure, in the gel phase, the frequency significantly shifts to lower values with the incorporation of 6 mol% CLX, indicating an increase in the number of trans conformers thus increasing the order of the system.…”

“…In our previous study, using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC), we have found that CLX exerts opposing effects on membrane order in a concentration dependent manner and it decreases the fluidity of the membrane at all concentrations. We have also proposed a possible location of CLX at low concentrations in the interfacial region and at high concentrations in the deeper hydrophobic region of the membrane [22].…”

Celecoxib-loaded liposomes: effect of cholesterol on encapsulation and in vitro release characteristics

“…When comparing the thermal effects of similar amounts of CLX and cholesterol, the differences in the endotherms of DSPC-only liposomes containing 18 mol% CLX and 5:1 DSPC/cholesterol empty liposomes (containing approx. CLX, on the other hand, is a much smaller molecule that again locates itself in the co-operativity region (at 18 mol%), but without any H-bond formation with the carbonyl groups [34]. CLX, on the other hand, is a much smaller molecule that again locates itself in the co-operativity region (at 18 mol%), but without any H-bond formation with the carbonyl groups [34].…”