| 19554429 |
Nojima Y, Suzuki Y, Yoshida K, Abe F, Shiga T, Takeuchi T, Sugiyama A, Shimizu H, Sato A: Lactoferrin conjugated with 40-kDa branched poly (ethylene glycol) has an improved circulating half-life. Pharm Res. 2009 Sep;26(9):2125-32. Epub 2009 Jun 25.
PURPOSE: We developed a lactoferrin conjugate by modifying bovine lactoferrin (bLF) with a 40-kDa branched poly (ethylene glycol) (PEG) molecule (designated 40 k-PEG-bLf), and we evaluated its in vitro activities and pharmacokinetic properties. MATERIALS AND METHODS: We prepared 40k-PEG-bLf by amino conjugation with N-hydroxysuccinimide-activated PEG. This conjugate was purified by cation exchange chromatography and its in vitro biological activities, such as iron binding, anti-inflammatory effects, and resistance to proteolytic enzymes were investigated. In vivo pharmacokinetics analyses, were also performed to examine the rate of clearance from the plasma in rats. RESULTS: The 40k-PEG-bLf conjugate was fully active in iron binding and exhibited 97.1 +/- 5.5% (mean +/- S.E., n = 6) of the original anti-inflammatory activity. The in vitro peptic susceptibility of 40 k-PEG-bLf revealed that the proteolytic half-life increased at least 6-fold that of unmodified LF. This PEGylated conjugate demonstrated a plasma half-life that was 8.7-fold longer than that of the unmodified bLF in rats. CONCLUSIONS: The 40k-PEG-bLf exhibited improved in vitro bioactivity and stability and enhanced pharmacokinetic properties as compared to those of the unmodified bLF and the 20 k-PEG-bLf conjugate, which was recently developed by PEGylation of bLF with a 20-kDa branched PEG [Nojima Y. et al. Bioconjugate Chem. 19:2253-2259 (2008)]. |
112(1,2,2,2) |