Organ distribution and tumor uptake of annamycin, a new anthracycline derivative with high affinity for lipid membranes, entrapped in multilamellar vesicles

Abstract

Annamycin (Ann) is a lipophilic, non-cross resistant anthracycline antibiotic that is easily amenable to formulation in a wide variety of liposomal carriers. We studied the organ distribution and tumor uptake of Ann entrapped in multilamellar vesicles (L-Ann), free annamycin (F-Ann), and doxorubicin (DOX) in C57BL/6 mice bearing advanced subcutaneous B16 melanoma tumors. L-Ann was composed of DMPC: DMPG: Ann at a molar ratio of 7:3:0.7. Mean particle size was 1.88±0.89 μm, and the entrapment efficiency was 93.08%±2.96%. F-Ann was prepared as a suspension (particle size ≤0.2 μm) in 10% DMSO. Drug 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 liver and kidney, six-fold 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 prolonged retention of Ann in tumor tissue compared with those of DOX. The results obtained indicate significant differences in organ distribution between L-Ann and DOX as a result of the higher affinity of Ann for lipid membranes and the use of the liposomes as a delivery system. The potential clinical relevance of the increased uptake of L-Ann in B16 tumors, lung, and brain is being investigated. © 1993 Springer-Verlag.