Nicolay K, Sautereau A M, Tocanne J F, Brasseur R, Huart P, Ruysschaert J M, de Kruijff B
Institute of Molecular Biology and Medical Biotechnology, University of Utrecht, The Netherlands.
Biochim Biophys Acta. 1988 May 24;940(2):197-208. doi: 10.1016/0005-2736(88)90195-2.
The interaction of a number of positively charged anti-tumor drugs with cardiolipin-containing model membranes has been investigated using 31P nuclear magnetic resonance (31P-NMR), differential scanning calorimetry (DSC) and monolayer techniques. It appeared that the ellipticines used (i.e., celiptium and 2-N-methylellipticinium), and also ethidium bromide, completely blocked Ca2+-induced HII phase formation in pure cardiolipin liposomes at molar ratios of drug-to-lipid of approx. 1:1. For the anthracyclines adriamycin and 4'-epi-adriamycin, a similar effect was observed, but now a 2:1 ratio was required. 31P-NMR experiments on dioleoylphosphatidylethanolamine/cardiolipin mixed liposomes indicated that the two anthracyclines, but not the other three drugs, were capable of inducing macroscopic phase separation into domains enriched in drug-cardiolipin complexes and domains enriched in the zwitterionic phospholipid species. DSC experiments on dipalmitoylphosphatidylcholine/cardiolipin mixtures led, with the exception of 2-N-methylellipticinium, to the same conclusion. Measurements of surface pressure and surface potential of cardiolipin monolayers at the air/water interface as well as conformational analysis of the various drug-cardiolipin recombinants showed that the ellipticines are deeply embedded in the acyl chain region of the bilayer, while the anthracyclines and ethidium bromide are preferentially localized in the interface. All drugs share an important electrostatic interaction with the negatively charged phosphates of cardiolipin.
利用31P核磁共振（31P-NMR）、差示扫描量热法（DSC）和单层技术，研究了多种带正电荷的抗肿瘤药物与含心磷脂的模型膜之间的相互作用。结果表明，所使用的玫瑰树碱（即蛇根碱和2-N-甲基玫瑰树碱）以及溴化乙锭，在药物与脂质的摩尔比约为1:1时，能完全阻止Ca2+诱导的纯心磷脂脂质体中HII相的形成。对于蒽环类药物阿霉素和4'-表阿霉素，也观察到了类似的效果，但此时所需的比例为2:1。对二油酰磷脂酰乙醇胺/心磷脂混合脂质体进行的31P-NMR实验表明，这两种蒽环类药物，而非其他三种药物，能够诱导宏观相分离，形成富含药物-心磷脂复合物的区域和富含两性离子磷脂种类的区域。对二棕榈酰磷脂酰胆碱/心磷脂混合物进行的DSC实验，除2-N-甲基玫瑰树碱外，也得出了相同的结论。对心磷脂单层在空气/水界面的表面压力和表面电位的测量，以及对各种药物-心磷脂重组体的构象分析表明，玫瑰树碱深深嵌入双层的酰基链区域，而蒽环类药物和溴化乙锭则优先定位于界面。所有药物都与心磷脂带负电荷的磷酸盐存在重要的静电相互作用。
