期刊
PHARMACEUTICAL RESEARCH
卷 32, 期 7, 页码 2428-2438出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-015-1635-0
关键词
endosome escape; gemcitabine; long-circulation; PEGylation; pH-sensitive liposomes (PSL); post-insertion
资金
- Marsden Fund by the Royal Society of New Zealand [UOA1201]
- University of Auckland, New Zealand
The in vitro and in vivo properties of PEGylated pH-sensitive liposomes (PSL) prepared by pre- and post-insertion techniques were investigated. A pre-insertion or post-insertion technique was used for PSL PEGylation. For the first time, confocal laser scanning microscopy coupled with a modified calcein self-quench assay was applied to evaluate the endosome escape capability. PSL cellular uptake was evaluated using macrophages and the cytotoxicity using a gemcitabine (model drug)-resistant MIA PaCa-2 cells. The pharmacokinetics of PSL encapsulated gemcitabine was investigated in rats. PEGylation reduced the pH-sensitivity in a concentration-dependent manner (0.5-5% mol). Both PEGylation methods reduced the uptake of PSL by macrophages by over 60%. Cytotoxicity was ranked in the order: post-inserted PSL a parts per thousand yen pre-inserted PSL > non-PSL > gemcitabine solution, consistent with the confocal microscopic observation and pH-sensitivity. Both pre and post-inserted PSL resulted in significant reductions (p < 0.05) in plasma clearance (58.6 and 38.4 ml/h/kg), increases in the area-under-the-concentration-time curve (56.9 and 87.1 mu M center dot h) and half-life (6.1 and 6.2 h) compared to gemcitabine solution (152.9 ml/h/kg, 22.2 mu M center dot h and 1.4 h). PEGylation by post-insertion offers advantages over pre-insertion to obtain PSL with enhanced pH-sensitivity, more effective intra-cytoplasmic delivery, and a superior pharmacokinetics.
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