Doxorubicin coupled to lactosaminated albumin: Effect of heterogeneity in drug load on conjugate disposition and hepatocellular carcinoma uptake in rats

Coupling to lactosaminated human albumin (L-HSA) makes doxorubicin (DOXO) an effective drug against chemically induced rat hepatocellular carcinomas (HCCs). In the conjugate there is a large heterogeneity in the number of DOXO molecules bound to one L-HSA molecule. After lyophilization, the molecules with the higher DOXO load form large complexes (C-DOXO(L)), whereas those with low drug load (C-DOXO(S)) have the size of the carrier L-HSA. In the present experiments, we demonstrated that in C-DOXO(L) the molecules are not linked by covalent bonds, but are strongly aggregated probably because of mutual drug–drug interaction between the DOXO residues. In healthy rats and in animals with HCCs which received the same dose (1 μg/g) of DOXO injected in C-DOXO(L) or in C-DOXO(S) forms, penetration of the drug in tumors and in tissues was more rapid after administration of the former complex. Three hours after injection of both conjugate forms the intracellular release of DOXO from the carrier was completed. The AUCs from 0.5 to 4 h of the levels of the released DOXO in HCCs, surrounding liver and bone marrow of animals injected with C-DOXO(L) were similar to those calculated in animals given C-DOXO(S). This suggests that after administration of the dose of DOXO used in the present experiments the conjugate molecules with lower or higher drug load can exert comparable pharmacological and toxic effects.