Comparison of the interaction of doxorubicin, daunorubicin, idarubicin and idarubicinol with large unilamellar vesicles. Circular dichroism study

Biochim Biophys Acta. 1998 Mar 6;1370(1):31-40. doi: 10.1016/s0005-2736(97)00241-1.


Doxorubicin, daunorubicin and other anthracycline antibiotics constitute one of the most important groups of drugs used today in cancer chemotherapy. The details of the drug interactions with membranes are of particular importance in the understanding of their kinetics of passive diffusion through the membrane which is itself basic in the context of multidrug resistance (MDR) of cancer cells. Anthracyclines are amphiphilic molecules possessing dihydroxyanthraquinone ring system which is neutral under the physiological conditions. Their lipophilicity depends on the substituents. The amino sugar moiety bears the positive electrostatic charge localised at the protonated amino nitrogen. The four anthracyclines used in this study doxorubicin, daunorubicin, idarubicin and idarubicinol (an idarubicin metabolite readily formed inside the cells) have the same amino sugar moiety, daunosamine, with pKa of 8.4. Thus, all drugs studied will exhibit very similar electrostatic interactions with membranes, while the major differences in overall drug-membrane behaviour will result from their hydrophobic features. Circular dichroism (CD) spectroscopy was used to understand more precisely the conformational aspects of the drug-membrane systems. Large unilamellar vesicles (LUV) consisting of phosphatidylcholine, phosphatidic acid (PA) and cholesterol, were used. The anthracycline-LUV interactions depend on the molar ratio of phospholipids per drug. At low molar ratios drug:PA, these interactions depend also on the anthracycline lipophilicity. Thus, both doxorubicin and daunorubicin bind to membranes as monomers and their CD signal in the visible is positive. However, doxorubicin with its very low lipophilicity binds to the LUV through electrostatic interactions, with the dihydroxyanthraquinone moiety being in the aqueous phase, while daunorubicin, which is more lipophilic is unable to bind only through electrostatic interactions and actually the hydrophobic interactions are the only detected. The highly hydrophobic idarubicin, forms within the bilayer a rather complex entity involving 2-3 molecules of idarubicin associated in the right-handed conformation, one cholesterol molecule and also molecule(s) of phosphatidic acid, as this special oligomeric species is not detected in the absence of negatively-charged phospholipids. Idarubicinol differs from idarubicin with CH(13)-OH instead of C(13)=O and its interactions with LUV are distinctly different. Its CD signal in the visible becomes negative and no self associations of the molecule within the bilayer could be detected. The variation of the sign of the Cotton effect (positive to negative) may derive from the changes in the C(6a)-C(7)-O(7)-C(1') dihedral angle. It is noteworthy that C(13)-OH group, which strongly favours formation of the dimeric species in aqueous solutions when compared to idarubicin prevent association inside the LUV bilayer. At high ratios of phospholipids per drug all of them are embedded within the bilayer as monomer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthracyclines / chemistry*
  • Circular Dichroism
  • Daunorubicin / analogs & derivatives
  • Daunorubicin / chemistry
  • Dimerization
  • Doxorubicin / chemistry
  • Idarubicin / chemistry
  • Lipid Bilayers / chemistry*
  • Liposomes / chemistry*
  • Membranes, Artificial
  • Models, Molecular
  • Solvents


  • Anthracyclines
  • Lipid Bilayers
  • Liposomes
  • Membranes, Artificial
  • Solvents
  • Doxorubicin
  • idarubicinol
  • Idarubicin
  • Daunorubicin