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.
Cheng
Xiaoyun
X
Department of Polymer Science and Engineering, Nanjing University, Nanjing, China.
Gao
Fengbo
F
Xiang
Jiawei
J
Jiang
Xiqun
X
Chen
Jiangning
J
Zhang
Junfeng
J
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