ANTHRACYCLINES WITH HIGH AFFINITY FOR LIPID MEMBRANES

Cell membrane events play an important role in modulating the cytotoxicity and resistance to anthracyline antibiotics. Membrane-targeted anthracyclines may potentiate the membrane-based mechanisms of cytotoxicity and result in a lower affinity for the protein-based mechanisms of drug efflux, which play a major role in mediating cell resistance. Structural requirements for an optimal anthracycline-lipid membrane affinity and for overcoming resistance to doxorubicin have been identified. This information will be used to design and synthesize new anthracycline antibiotics with a high affinity for lipid membranes and partially not cross-resistant with doxorubicin. Since most compounds are expected to be highly lipophilic, liposomes of different composition and size and with tumor targeting properties will be explored as natural carriers for the new analogs synthesized. The antitumor activity, toxicity, pharmacokinetics, organ distribution, and tumor uptake of several prototype liposomal anthracycline preparations will be studied and compared with those of doxorubicin and the non-entrapped drugs. The evaluation of the efficacy of these preparation in the targeted therapy of liver metastases will receive particular attention. The affinity for lipid membranes and the effects on the cell membrane of sensitive and resistant tumor cells will be carefully examined, and the role of the membrane effects in mediating tumor cell cytotoxicity assessed. The study will define the potential of liposomes as carriers of new lipophilic anthracyclines antibiotics and lead to the selection of candidate preparation for clinical development. The information generated will be essential in further understanding the role of the cell membrane in modulating the biological activity of this group of compounds and in providing rational guidance for improving the design and use of drug carriers for antitumor agents.