A pegylated liposomal platform: pharmacokinetics, pharmacodynamics, and toxicity in mice using doxorubicin as a model drug.
Aims were to observe pharmacokinetics, pharmacodynamics, and toxicity for constructing a Sino-pegylated liposomal platform. Human hepatocarcinoma cells (Bel7402) and murine hepatocarcinoma cells (H(22)) were used for the cytotoxicity assay and the in vivo solid xenograft tumor model in mice, respectively. Pharmacokinetic results in mice showed that the pegylated liposomal doxorubicin markedly prolonged the blood circulation of doxorubicin. Elimination half-time (T(1/2,gamma)) of pegylated, regular liposomal doxorubicin and free doxorubicin were 46.09 +/- 14.44, 26.04 +/- 3.34, and 23.72 +/- 5.13 h, respectively. The area under the concentration-time curves (AUC(0- infinity )) (h. microg/g) of the pegylated and regular liposomal doxorubicin were 6.8- and 2.6-fold higher than that of free doxorubicin, respectively. Cytotoxicity and antitumor activity in vivo indicated that activity of the pegylated liposomal doxorubicin was higher than that of the regular or the free one, respectively. After two weeks of tail intravenous injection of the pegylated liposomal doxorubicin at a single dose of 10 mg/kg, no significant damage was observed in gastric, intestinal mucosa, and heart muscle, but pronounced damages were found in the control group after dosing free doxorubicin. The results demonstrate that the pegylated liposomes improve the efficacy of toxics and reduce the toxicity, therefore providing favorable evidence for building a pegylated liposomal platform.
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100083, P.R. of China.
Wan-Liang
WL
Lu
Xian-Rong
XR
Qi
Qiang
Q
Zhang
Rong-Yu
RY
Li
Gui-Lin
GL
Wang
Rui-Juan
RJ
Zhang
Shu-Li
SL
Wei
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000633:toxicity; D019540:Area Under Curve; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000633:toxicity; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D008081:Liposomes; D008297:Male; D051379:Mice; D009206:Myocardium / Q000473:pathology; D011092:Polyethylene Glycols; D013997:Time Factors; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D008081:Liposomes; D011092:Polyethylene Glycols; D004317:Doxorubicin