title: Doxorubicin coupled to lactosaminated albumin: effect of heterogeneity in drug load on conjugate disposition and hepatocellular carcinoma uptake in rats.
abstract: 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-DOXOL), whereas those with low drug load (C-DOXOS) have the size of the carrier L-HSA. In the present experiments, we demonstrated that in C-DOXOL 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 microg/g) of DOXO injected in C-DOXOL or in C-DOXOS 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 4h of the levels of the released DOXO in HCCs, surrounding liver and bone marrow of animals injected with C-DOXOL were similar to those calculated in animals given C-DOXOS. 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.
authors.affiliation: Department of Experimental Pathology, University of Bologna, Via San Giacomo 14, 40126 Bologna, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Di Stefano
authors.forename: Luigi
authors.initials: L
authors.lastname: Fiume
authors.forename: Michele
authors.initials: M
authors.lastname: Baglioni
authors.forename: Corrado
authors.initials: C
authors.lastname: Busi
authors.forename: Luigi
authors.initials: L
authors.lastname: Bolondi
authors.forename: Claudio
authors.initials: C
authors.lastname: Farina
authors.forename: Filippo
authors.initials: F
authors.lastname: Mori
authors.forename: Pasquale
authors.initials: P
authors.lastname: Chieco
authors.forename: Milena
authors.initials: M
authors.lastname: Pariali
authors.forename: Felix
authors.initials: F
authors.lastname: Kratz
authors.forename: Laura
authors.initials: L
authors.lastname: Molin
authors.forename: Stefano
authors.initials: S
authors.lastname: Salmaso
authors.forename: Paolo
authors.initials: P
authors.lastname: Caliceti
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001853:Bone Marrow / Q000737:chemistry / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002850:Chromatography, Gel; D002853:Chromatography, Liquid; D002942:Circular Dichroism; D004317:Doxorubicin / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D008970:Molecular Weight; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000737:chemistry*
chemical_list: D012709:Serum Albumin; C046912:lactosaminated serum albumin; D004317:Doxorubicin