Boman N L, Mayer L D, Cullis P R
University of British Columbia, Biochemistry Department, Canada.
Biochim Biophys Acta. 1993 Nov 7;1152(2):253-8. doi: 10.1016/0005-2736(93)90256-y.
The influence of lipid composition, internal pH and internal buffering capacity on the retention properties of vincristine loaded into large unilamellar vesicle (LUV) systems in response to transmembrane pH gradients has been assessed. It is shown that increasing the (saturated) acyl chain length of the phosphatidylcholine molecule, increasing the internal buffering capacity, and decreasing the internal pH all result in increased drug retention. Further, a study of the pH dependence on the rates of accumulation indicate that uptake proceeds via the neutral form of the vincristine molecule. This uptake is associated with an activation energy of 37 kcal/mol for DSPC/Chol LUVs. It is shown that the major improvement in drug retention in vitro is achieved by employing low initial internal pH values, where 90% retention is obtained over 24 h for an initial internal pH of 2. Improved retention in vivo was also observed where a drug-to-lipid ratio approx. 4-fold greater at 24 h was maintained.
评估了脂质组成、内部pH值和内部缓冲能力对响应跨膜pH梯度加载到大型单层囊泡（LUV）系统中的长春新碱保留特性的影响。结果表明，增加磷脂酰胆碱分子的（饱和）酰基链长度、增加内部缓冲能力以及降低内部pH值均会导致药物保留增加。此外，对pH对积累速率的依赖性研究表明，摄取是通过长春新碱分子的中性形式进行的。对于DSPC/Chol LUVs，这种摄取与37 kcal/mol的活化能相关。结果表明，通过采用低初始内部pH值可在体外实现药物保留的主要改善，当初始内部pH值为2时，在24小时内可实现90%的保留率。在体内也观察到了改善的保留情况，其中在24小时时维持的药物与脂质比率大约高4倍。
