In vitro cytotoxicity, pharmacokinetics and tissue distribution in rats of MXN-004, a novel conjugate of polyethylene glycol and SN38

Abstract

1. MXN-004 is a water-soluble PEGylated 7-ethyl-10-hydroxy-camptothecin (SN38). The aim of this study was to evaluate the in vitro cytotoxicity of MXN-004 and investigate pharmacokinetics and tissue distribution of MXN-004 and its active metabolite SN38 in rats.

2. In vitro cytotoxicity of MXN-004 was tested in A549, HepG2 and Caco-2 cancer cell lines by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and compared with irinotecan. The pharmacokinetics and tissue distribution of MXN-004, irinotecan and their identical active metabolite SN38 were investigated after intravenous administration of MXN-004 and irinotecan at a same dose level of 16 μmol/kg in rats.

3. In vitro cytotoxicity study showed that MXN-004 was more potent in comparison with irinotecan. In rats, MXN-004 exhibited a longer half-life (sixfold) and much greater V_ss as compared with irinotecan. The AUC_0–∞, T_1/2 and C_max of SN38 after intravenous administration of MXN-004 were higher than those of irinotecan (3.5-, 1.92- and 10.6-fold, respectively). In addition, the concentrations of SN38 released from MXN-004 were significantly higher in all tissues than those from irinotecan, especially in the lung.

4. These results suggested that MXN-004 might be a more potential water-soluble antitumor agent with prolonged half-life of SN38 compared to irinotecan.

• Cytotoxicity
• PEGylation
• pharmacokinetics
• SN38
• topoisomerase I inhibitors

Acknowledgements

The authors are thankful to Chunfeng Wang, Wei Zhang and Yanli Wen for their help in this study.