A differential scanning calorimetry study of phosphocholines mixed with paclitaxel and its bromoacylated taxanes

High sensitivity differential scanning calorimetry (DSC) was used to invest igate the thermotropic phase properties of binary mixtures of disaturated p hosphocholines (PCs) and alpha-bromoacyl taxane derivatives. The alpha-brom oacyl taxanes were synthesized as hydrolyzable hydrophobic prodrugs of pacl itaxel. The PCs used were 1,2-dimyristoyl-sn-glycero-3-phosphatidyl-choline (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and I,2-di stearoyl-sn-glycero-3-phosphatidylcholine (DSPC), The bromoacyl chain lengt hs of the taxane prodrugs were varied from 6 to 12 or 16 carbons. For compa rison, paclitaxel and PC mixtures were also examined. DSC data from DPPC an d bromoacyl taxane mixtures showed a complete abolition of the pretransitio n and significant broadening of the main phase transition with increasing a mounts of bromoacyl taxane prodrugs, The effects were more pronounced with the long-chain compared to the short-chain prodrugs. Under equivalent DSC c onditions, the short-chain DMPC showed greater changes in thermotropic phas e behavior than with DPPC on taxane addition, suggesting an enhanced degree of association with the fluid-type bilayers. Under similar conditions, the long-chain DSPC bilayers showed a far less significant change in phase beh avior on taxane addition than DPPC. These changes were also chain length-de pendent for both the PCs and the taxane prodrugs, In contrast, PC and pacli taxel (lacking the acyl chain) mixtures under similar conditions showed ins ignificant changes in the endotherms, suggesting only slight insertion of t he molecule into the PC bilayers. From the DSC data it is apparent that tax ane prodrugs solvated in DMPC bilayers more than in DPPC and DSPC bilayers, and taxane prodrugs with longer acyl chains were able to associate with PC s better than those with shorter chain prodrugs. DSC data also suggest that paclitaxel was poorly associated with any of the PCs. In general, the amou nt of taxane association with bilayers decreased in order: DMPC > DPPC >> D SPC. In contrast, the transition enthalpy (Delta H) of DMPC, DPPC, and DSPC mixtures with paclitaxel showed significantly lower enthalpies than with t axane prodrugs. Taken together, the DSC data suggest that the acyl chains o f paclitaxel prodrugs have some access into the bilayers via alignment with the acyl chain of the PC component.