Galactosylated α,β-poly[(2-hydroxyethyl)-L-aspartamide]-bound doxorubicin: improved antitumor activity against hepatocellular carcinoma with reduced hepatotoxicity.
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.
Department of Polymer Science and Engineering, Nanjing University, Nanjing, China.
Xiaoyun
X
Cheng
Fengbo
F
Gao
Jiawei
J
Xiang
Xiqun
X
Jiang
Jiangning
J
Chen
Junfeng
J
Zhang
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004317:Doxorubicin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D004337:Drug Carriers / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005690:Galactose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D006367:HeLa Cells; D006331:Heart Diseases / Q000139:chemically induced; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D010455:Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D018675:Toxicity Tests
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D010455:Peptides; C008965:alpha,beta-poly((2-hydroxyethyl)-aspartamide); D004317:Doxorubicin; D005690:Galactose