Ali S, Minchey S, Janoff A, Mayhew E
The Liposome Company, Inc., One Research Way, Princeton, NJ 08540, USA.
Biophys J. 2000 Jan;78(1):246-56. doi: 10.1016/S0006-3495(00)76588-X.
High sensitivity differential scanning calorimetry (DSC) was used to investigate the thermotropic phase properties of binary mixtures of disaturated phosphocholines (PCs) and alpha-bromoacyl taxane derivatives. The alpha-bromoacyl taxanes were synthesized as hydrolyzable hydrophobic prodrugs of paclitaxel. The PCs used were 1, 2-dimyristoyl-sn-glycero-3-phosphatidyl-choline (DMPC), 1, 2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and 1, 2-distearoyl-sn-glycero-3-phosphatidylcholine (DSPC). The bromoacyl chain lengths of the taxane prodrugs were varied from 6 to 12 or 16 carbons. For comparison, paclitaxel and PC mixtures were also examined. DSC data from DPPC and bromoacyl taxane mixtures showed a complete abolition of the pretransition and significant broadening of the main phase transition with increasing amounts of bromoacyl taxane prodrugs. The effects were more pronounced with the long-chain compared to the short-chain prodrugs. Under equivalent DSC conditions, the short-chain DMPC showed greater changes in thermotropic phase 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 behavior on taxane addition than DPPC. These changes were also chain length-dependent for both the PCs and the taxane prodrugs. In contrast, PC and paclitaxel (lacking the acyl chain) mixtures under similar conditions showed insignificant changes in the endotherms, suggesting only slight insertion of the molecule into the PC bilayers. From the DSC data it is apparent that taxane prodrugs solvated in DMPC bilayers more than in DPPC and DSPC bilayers, and taxane prodrugs with longer acyl chains were able to associate with PCs better than those with shorter chain prodrugs. DSC data also suggest that paclitaxel was poorly associated with any of the PCs. In general, the amount of taxane association with bilayers decreased in order: DMPC > DPPC >> DSPC. In contrast, the transition enthalpy (DeltaH) of DMPC, DPPC, and DSPC mixtures with paclitaxel showed significantly lower enthalpies than with taxane prodrugs. Taken together, the DSC data suggest that the acyl chains of paclitaxel prodrugs have some access into the bilayers via alignment with the acyl chain of the PC component.
采用高灵敏度差示扫描量热法（DSC）研究了二饱和磷酸胆碱（PCs）与α-溴代酰基紫杉烷衍生物二元混合物的热致相性质。α-溴代酰基紫杉烷被合成为紫杉醇的可水解疏水前药。所用的PCs为1,2-二肉豆蔻酰-sn-甘油-3-磷脂酰胆碱（DMPC）、1,2-二棕榈酰-sn-甘油-3-磷脂酰胆碱（DPPC）和1,2-二硬脂酰-sn-甘油-3-磷脂酰胆碱（DSPC）。紫杉烷前药的溴代酰基链长度从6到12或16个碳不等。为作比较，还检测了紫杉醇与PCs的混合物。DPPC与溴代酰基紫杉烷混合物的DSC数据显示，随着溴代酰基紫杉烷前药含量的增加，预转变完全消失，主相变显著变宽。与短链前药相比，长链前药的效果更明显。在相同的DSC条件下，添加紫杉烷后，短链的DMPC在热致相行为上的变化比DPPC更大，表明其与流体型双层膜的缔合程度增强。在类似条件下，添加紫杉烷后，长链DSPC双层膜在相行为上的变化远不如DPPC显著。这些变化对于PCs和紫杉烷前药来说也都依赖于链长。相比之下，在类似条件下，PCs与紫杉醇（不含酰基链）的混合物在吸热方面变化不显著，表明该分子仅轻微插入PC双层膜中。从DSC数据可以明显看出，紫杉烷前药在DMPC双层膜中的溶剂化程度高于在DPPC和DSPC双层膜中的程度，并且酰基链较长的紫杉烷前药比酰基链较短的前药与PCs的缔合能力更强。DSC数据还表明，紫杉醇与任何一种PCs的缔合都很差。一般来说，紫杉烷与双层膜的缔合量按以下顺序降低：DMPC＞DPPC＞＞DSPC。相比之下，DMPC、DPPC和DSPC与紫杉醇混合物的转变焓（ΔH）显著低于与紫杉烷前药混合物的焓。综合来看，DSC数据表明，紫杉醇前药的酰基链通过与PC组分的酰基链排列，在一定程度上进入了双层膜。
