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.
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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)
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Chemical References |
- Antibiotics, Antineoplastic
- Drug Carriers
- Peptides
- alpha,beta-poly((2-hydroxyethyl)-aspartamide)
- Doxorubicin
- Galactose
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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
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