Journal
PHARMACEUTICAL RESEARCH
Volume 33, Issue 7, Pages 1628-1637Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-016-1902-8
Keywords
drug loading; endosome escape; gemcitabine; long-circulation; pH-sensitive liposomes (PSL)
Funding
- Marsden Fund by the Royal Society of New Zealand [UOA1201]
- Auckland Medical Research Fund [1113026]
- University of Auckland, New Zealand
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To develop pH-sensitive liposomes (PSL) containing a high content of gemcitabine; and to investigate whether drug loading (DL) would alter the in vitro and pharmacokinetic properties. PSL with a high DL were obtained using a modified small-volume incubation method. The DL effects on drug release rate and in vitro cytotoxicity of PSL were evaluated using MIA PaCa-2 pancreatic cancer cells and their pharmacokinetics investigated in rats. The highest DL of 4.5 +/- 0.1% was achieved for gemcitabine in PSL with 145 +/- 5 nm diameter. DL did not alter the in vitro release rate from PSL. The IC50 (48 h) of PSL (DL 0.5 and 4.5%) and non pH-sensitive liposomes (NPSL, DL 4.2%) were 1.1 +/- 0.1, 0.7 +/- 0.1 and 37.0 +/- 7.5 mu M, respectively. The PSL resulted in a 4.2-fold increase in its elimination half-life (6.2 h) compared to gemcitabine solution (1.4 h) in rats. No significant difference in pharmacokinetic parameters was observed between the two PSL (DL 0.5 and 4.5%). The PSL offered advantages over NPSL in restoring the sensitivity of pancreatic cancer cells to gemcitabine without requiring a high DL. DL in the PSL did not alter release rate, cytotoxicity or their long-circulating properties.
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