Simple and efficient liposomal encapsulation of topotecan by ammonium sulfate gradient: stability, pharmacokinetic and therapeutic evaluation.
Topotecan (TPT), a topoisomerase I inhibitor, is presently undergoing clinical evaluation worldwide. Previous studies have shown that entrapping TPT within multi-lamellar vesicle liposome can stabilize the lactone moiety, which is structurally important for biological activity. However, low drug:lipid ratios due to the amphipathic character and small entrapment volume in the unilamellar vesicle limits the development of pharmaceutically acceptable liposomal formulation. With an aim to improve on this drawback, we herein describe a method that utilizes the ammonium sulfate gradient to entrap TPT into liposomes. By this method, the encapsulation efficiency was over 90% and a drug:lipid molar ratio as high as 1:5.4 was reached. In comparison with free drug, liposome-encapsulated TPT is more stable in physiological conditions and shows higher in vitro cytotoxicity. Because of increased blood circulation time, the initial plasma concentration and area under the plasma concentration of liposomal drugs were 14 and 40 times, respectively, of those of free drug. Furthermore, liposome encapsulation enhanced the antitumor activity of TPT in syngeneic murine C-26 and human HTB-9 xenograft models in vivo. At a dose of 5 mg/kg, the tumor growth delay of liposomal formulation was significantly than that of free TPT. Based on these results, we believe that this liposomal TPT formulation is worthy of further clinical study.
Graduate Institute of Biochemistry and Molecular Biology, National Taiwan University Hospital, Taipei 10016, Taiwan, ROC.
Jun-Jen
JJ
Liu
Ruey-Long
RL
Hong
Wen-Fang
WF
Cheng
Keelung
K
Hong
Fu-Hsiung
FH
Chang
Yun-Long
YL
Tseng
D000465:Algorithms; D000645:Ammonium Sulfate / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004337:Drug Carriers; D004339:Drug Compounding / Q000379:methods*; D004355:Drug Stability; D006801:Humans; D007202:Indicators and Reagents; D007783:Lactones / Q000737:chemistry; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D019772:Topotecan / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004337:Drug Carriers; D007202:Indicators and Reagents; D007783:Lactones; D008081:Liposomes; D019772:Topotecan; D000645:Ammonium Sulfate