CATION-PI INTERACTIONS OF ANTHRACYCLINE DRUGS

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DESCRIPTION: The proposed investigations seek to identify the factors that govern the non-covalent interactions of anthracycline antibiotics with cell membranes. These drug-membrane associations play a critical role in the therapeutic activity of the drugs, governing cytotoxic selectivity between normal and tumor tissue, dictating cell access, and affecting the development of multiple drug resistance by tumor cells. Membrane properties will be identified to account for (a) the existence of both surface-bound and lipid-intercalated interactions of anthracycline drugs with cell membranes and (b) the substantial decrease in the binding of anthracycline antibiotics to the membranes of drug-resistant cells as compared to those of drug-sensitive cells. Surfactant -based reverse micellar systems will serve as well characterized models of both the biological membranes with which these drugs interact and the liposomal systems employed as delivery vehicles for these drugs. The partitioning and binding of anthracycline drugs and analogs with these reverse micelle systems will be assessed with fluorescence spectroscopic techniques. Two specific hypotheses will be tested: (1) The cation-pi interaction is significant non-covalent binding force that mediates the partioning and release of aromatic drugs within surfactant-based drug delivery systems and within biological membranes. (2) The lipid head group size and charge and the lipid tail structure and linear dimensions influence the extent and mode of binding and partitioning of anthracycline drugs in cells and liposomes. Differential interactions of various combinations of anthracyclines and reverse micelle systems will reveal the correspondence between drug structure and partitioning and the role of surfactant parameters in dictating drug-membrane interactions. These results will provide a greater understanding of anthracycline-membrane interactions for future optimization of anthracycline activity.