title: Coupling of lactose molecules to the carrier protein hinders the spleen and bone marrow uptake of doxorubicin conjugated with human albumin.
abstract: Several attempts have been made to enhance doxorubicin (DOXO) concentrations in tumour cells by drug conjugation with human albumin (HSA). HSA-DOXO has the drawback of causing DOXO accumulation in spleen and bone marrow, with a consequent leucopoenia not produced when lactose molecules are coupled to the carrier protein. In the present experiments we demonstrated that the effect of HSA lactosamination is not a consequence of a more rapid disappearance from the bloodstream of the lactosaminated conjugate (L-HSA-DOXO), which is rapidly internalized by the liver through the asialoglycoprotein receptor, but is due to a hindered uptake by spleen and bone marrow cells caused by the coupled lactose molecules. Experiments in vitro showed that HSA-DOXO produced an inhibition of murine macrophage proliferation not caused by L-HSA-DOXO. This result can be explained by higher amounts of the former conjugate entering in these cells and suggests macrophages as the cell type responsible for the spleen and bone marrow internalization of HSA-DOXO hindered by lactose coupling. Importantly, lactosamination of HSA did not reduce the marked uptake of HSA-DOXO by chemically induced rat hepatocellular carcinoma. L-HSA-DOXO, by avoiding DOXO accumulation in bone marrow is an attractive candidate for clinical trials against tumors which were found to actively internalize this conjugate in laboratory animals, such as hepatocellular carcinoma.
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: Pasquale
authors.initials: P
authors.lastname: Chieco
authors.forename: Felix
authors.initials: F
authors.lastname: Kratz
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mattioli
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism*; D002250:Carbon Radioisotopes; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D049109:Cell Proliferation / Q000187:drug effects; D004052:Diethylnitrosamine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D004337:Drug Carriers; D005260:Female; D006801:Humans; D007785:Lactose / Q000737:chemistry*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000737:chemistry*; D013154:Spleen / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D002250:Carbon Radioisotopes; D004337:Drug Carriers; D012709:Serum Albumin; C046912:lactosaminated serum albumin; D004052:Diethylnitrosamine; D004317:Doxorubicin; D007785:Lactose