Coupling of lactose molecules to the carrier protein hinders the spleen and bone marrow uptake of doxorubicin conjugated with human albumin.
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.
Di Stefano
Giuseppina
G
Department of Experimental Pathology, University of Bologna, via San Giacomo, 14-40126 Bologna, Italy.
Fiume
Luigi
L
Baglioni
Michele
M
Busi
Corrado
C
Chieco
Pasquale
P
Kratz
Felix
F
Mattioli
Alessandro
A
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
D000903:Antibiotics, Antineoplastic; D002250:Carbon Radioisotopes; D004337:Drug Carriers; D012709:Serum Albumin; C046912:lactosaminated serum albumin; D004052:Diethylnitrosamine; D004317:Doxorubicin; D007785:Lactose