ORGAN DISTRIBUTION AND TUMOR UPTAKE OF ANNAMYCIN, A NEW ANTHRACYCLINEDERIVATIVE WITH HIGH-AFFINITY FOR LIPID-MEMBRANES, ENTRAPPED IN MULTILAMELLAR VESICLES

Annamycin (Ann) is a lipophilic, non-cross resistant anthracycline ant ibiotic that is easily amenable to formulation in a wide variety of li posomal carriers. We studied the organ distribution and tumor uptake o f Ann entrapped in multilamellar vesicles (L-Ann), free annamycin (F-A nn), and doxorubicin (DOX) in C57BL/6 mice bearing advanced subcutaneo us B16 melanoma tumors. L-Ann was composed of DMPC: DMPG: Ann at a mol ar ratio of 7:3:0.7. Mean particle size was 1.88 +/- 0.89 mum, and the entrapment efficiency was 93.08% +/- 2.96%. F-Ann was prepared as a s uspension (particle size less-than-or-equal-to 0.2 mum) in 10% DMSO. D rug levels were measured by fluorescence spectrometry after extraction with chloroform. The extraction ratio ranged between 60% and 90% for both drugs in most tissues. Compared with those of DOX, organ AUCs of L-Ann were threefold higher in plasma and brain, twofold higher in liv er and kidney, sixfold higher in lung, ninefold higher in spleen, and tenfold higher in B16 tumors. Compared with F-Ann, organ AUCs of L-Ann were twofold higher in plasma, liver, and B16 tumors and were twofold lower in brain. Heart AUCs were similar with all three drugs. Higher tumor uptake was associated with a faster penetration and more prolong ed retention of Ann in tumor tissue compared with those of DOX. The re sults obtained indicate significant differences in organ distribution between L-Ann and DOX as a result of the higher affinity of Ann for li pid membranes and the use of the liposomes as a delivery system. The p otential clinical relevance of the increased uptake of L-Ann in B16 tu mors, lung, and brain is being investigated.