Hydroxyethyl starch-10-hydroxy camptothecin conjugate: synthesis, pharmacokinetics, cytotoxicity and pharmacodynamics research.
10-hydroxy camptothecin (10-HCPT) is an antitumor agent effective in the treatment of several solid tumors but its use is hampered by poor water solubility, low lactone stability, short plasma half-life and dose-limiting toxicity. In this study, 10-HCPT-hydroxyethyl starch (HES) conjugate was prepared to overcome these limits of 10-HCPT. The solubility of 10-HCPT conjugate was 0.72 mg/ml, about 100 times to free 10-HCPT. The 10-HCPT conjugate showed good sustained release effect in phosphate-buffered saline (PBS), rat plasma and liver homogenate. Meanwhile, 10-HCPT-HES conjugate achieved much lower IC50 and higher cytotoxicity effects than the free 10-HCPT on Hep-3B liver cancer cells. The pharmacokinetics results of 10-HCPT-HES conjugate demonstrated that the biological half-life of 10-HCPT was increased from 10 min to 4.38 h and the bioavailability was 40 times higher than the commercial 10-HCPT injection. The pharmacodynamics results indicated that 10-HCPT-HES conjugate had a better antitumor efficiency against nude mouse with Hep-3B tumor than the commercial 10-HCPT injection, and the inhibition ratio of tumor was 83.9 and 27.8%, respectively, at the same administration dosage. These findings suggest that 10-HCPT-HES conjugate is a promising drug delivery system providing improved long circulating effect, greater stability and better antitumor effect.
a School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China and.
Guofei
G
Li
a School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China and.
Cuifang
C
Cai
b Pharmacy, Liaoning Tumor Hospital , Shenyang , China.
Yingjie
Y
Qi
a School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China and.
Xing
X
Tang
D061605:Administration, Intravenous; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002166:Camptothecin / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D006207:Half-Life; D006895:Hydroxyethyl Starch Derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015552:Injections, Intralesional; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D012995:Solubility
D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; D006895:Hydroxyethyl Starch Derivatives; D002166:Camptothecin
10-hydroxy camptothecin; conjugate; hydroxyethyl starch; pharmacodynamics; pharmacokinetics