Effect of vesicle size and lipid composition on the in vivo tumor selectivity and toxicity of the non-cross-resistant anthracycline annamycin incorporated in liposomes.

Annamycin (Ann) is a non-cross-resistant lipophilic anthracycline antiobiotic optimally suited for liposome delivery. We studied how vesicle size and presence of phospholipids with a high phase transition temperature and monosialoganglioside (GM I) in the liposome bilayers affect the pharmacokinetics, tumor selectivity and toxicity of Ann. Entrapment of Ann in multilamellar vesicles (L-Ann) resulted in a 20% lower heart AUC and a 30-40% higher tumor and liver AUC. Reduction of the liposome size from 1.6 to 0.03 microns increased Ann plasma circulation time and tumor AUC by 2-fold, enhanced Ann tumor selectivity and decreased Ann subacute toxicity by 2-fold. The presence of phospholipids with a high phase transition temperature and GMI in the liposome bilayers further prolonged Ann plasma circulation time by 2- to 4-fold, did not increase Ann tumor AUC and moderately increased Ann subacute toxicity. The anti-tumor activity of Ann correlated with the tumor AUC achieved with each particular formulation. Our results strongly suggest that vesicle size may be an important determinant of the therapeutic index of liposomal Ann, but they fail to demonstrate a beneficial tumor-targeting effect of liposomes composed of GMI and phospholipids with a high phase transition temperature, as has been reported for the hydrophilic parent compound doxorubicin.