title: Development of Long-Circulating pH-Sensitive Liposomes to Circumvent Gemcitabine Resistance in Pancreatic Cancer Cells.
abstract: 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 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%).
  
  
  
  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.
authors.affiliation: School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: James W
authors.initials: JW
authors.lastname: Paxton
authors.affiliation: School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand. z.wu@auckland.ac.nz.
authors.forename: Zimei
authors.initials: Z
authors.lastname: Wu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D065546:Drug Liberation / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000737:chemistry* / Q000494:pharmacology*; D010179:Pancreas / Q000187:drug effects*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010316:Particle Size; D019999:Pharmaceutical Solutions / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000093542:Gemcitabine
chemical_list: D008081:Liposomes; D019999:Pharmaceutical Solutions; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: drug loading; endosome escape; gemcitabine; long-circulation; pH-sensitive liposomes (PSL)