Hongtao Xu1, James W Paxton2, Zimei Wu3. 1. School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand. 2. Department of Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. 3. School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand. z.wu@auckland.ac.nz.
Abstract
PURPOSES: 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. METHODS: 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. RESULTS: 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 μM, 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%). CONCLUSION: 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. Graphical Abstract ᅟ.
PURPOSES: 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. METHODS: 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. RESULTS: 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 μM, 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%). CONCLUSION: 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. Graphical Abstract ᅟ.
Entities:
Keywords:
drug loading; endosome escape; gemcitabine; long-circulation; pH-sensitive liposomes (PSL)
Authors: Wenli Zhang; Guangji Wang; James R Falconer; Bruce C Baguley; John P Shaw; Jianping Liu; Hongtao Xu; Esther See; Jianguo Sun; Jiye Aa; Zimei Wu Journal: Pharm Res Date: 2014-10-30 Impact factor: 4.200
Authors: Ralph Graeser; Christian Bornmann; Norbert Esser; Vittorio Ziroli; Peter Jantscheff; Clemens Unger; Ulrich T Hopt; Christoph Schaechtele; Ernst von Dobschuetz; Ulrich Massing Journal: Pancreas Date: 2009-04 Impact factor: 3.327