Galactosylated α,β-poly[(2-hydroxyethyl)-L-aspartamide]-bound doxorubicin: improved antitumor activity against hepatocellular carcinoma with reduced hepatotoxicity.

Abstract

Galactosyl-terminated drug carriers are known to enhance drug accumulation in the liver, while possible accompanying hepatic toxicity is usually not clarified. This study developed a galactosyl-α,β-poly[(2-hydroxyethyl)-L-aspartamide]-doxorubicin conjugate (Gal-PHEA-DOX) and investigated its therapeutic efficacy and safety in orthotopic hepatocellular carcinoma-bearing mice. Gal-PHEA-DOX had a galactosylation degree of 7.5 mol% and a DOX content of 8.9 wt%. A biodistribution study showed that Gal-PHEA-DOX sustainedly circulated in the plasma and highly accumulated in hepatocarcinoma. Free drug liberated from Gal-PHEA-DOX was relatively low in the liver and heart as compared with that of the DOX administration. The Gal-PHEA-DOX conjugate showed superior cytotoxicity against the hepatocellular carcinoma cell line HepG2 as compared with the nongalactosylated PHEA-DOX conjugate. Gal-PHEA-DOX exhibited comparable antitumor activity with PHEA-DOX in the S180-bearing mice, but more effective than PHEA-DOX or DOX in the Heps-bearing mice with negligible detrimental effect in the liver remnant. A systemic toxicity study showed that this conjugate did not show either cytotoxicity or hepatotoxicity at a relatively high dose, which would be harmful for free DOX. These results suggest that the Gal-PHEA-DOX conjugate has great potential for use in hepatocellular carcinoma chemotherapy because of its enhanced antitumor effect with reduced systemic toxicity including hepatotoxicity.

• Authors: Xiaoyun Cheng, Fengbo Gao, Jiawei Xiang, Xiqun Jiang, Jiangning Chen, Junfeng Zhang
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 22 Issue 2 Pg. 136-47 (Feb 2011) ISSN: 1473-5741 [Electronic] England
• PMID: 20966743 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Drug Carriers
• Peptides
• alpha,beta-poly((2-hydroxyethyl)-aspartamide)
• Doxorubicin
• Galactose

Topics

• Animals
• Antibiotics, Antineoplastic (administration & dosage, pharmacokinetics, toxicity)
• Cell Line, Tumor
• Chemical and Drug Induced Liver Injury (etiology)
• Doxorubicin (administration & dosage, analogs & derivatives, pharmacokinetics, toxicity)
• Drug Carriers (administration & dosage, pharmacokinetics, toxicity)
• Drug Screening Assays, Antitumor
• Female
• Galactose (administration & dosage, analogs & derivatives, pharmacokinetics, toxicity)
• HeLa Cells
• Heart Diseases (chemically induced)
• Humans
• Liver Neoplasms, Experimental (drug therapy, metabolism)
• Mice
• Mice, Inbred ICR
• Peptides (administration & dosage, pharmacokinetics, toxicity)
• Toxicity Tests