title: Nanocrystal formulations of a poorly soluble drug. 2. Evaluation of nanocrystal liver uptake and distribution after intravenous administration to mice.
abstract: A stabilized high drug load intravenous formulation could allow compounds with less optimal pharmacokinetic profiles to be developed. Polyethylene glycol (PEG)-ylation is a frequently used strategy for particle delivery systems to avoid the liver, thereby extending blood circulation time. The present work reports the mouse in vivo distribution after i.v. administration of a series of nanocrystals prepared with the bead milling technique and PEG-ylated with DSPE-PEG2000 and Pluronic F127, with and without polyvinylpyrrolidone K30 (PVP)/Aerosol OT (AOT) as primary stabilizers. While all formulations were cleared significantly faster than expected from nanocrystal dissolution alone, purely DSPE-PEG2000 PEG-ylated particles displayed prolonged circulation time (particles elimination half-life of 9min) compared to DSPE-PEG2000/PVP/AOT formulation (half-life of 3min). The two Pluronic F127 stabilized formulations displayed similar half-lives (9min with and without PVP/AOT, respectively). Whole tissue kinetics shows that clearance of particles could be attributed to accumulation in the liver. A separate in vivo study addressed the liver cell distribution after administration. Dissolved compound accumulated in hepatocytes only, while particles were distributed between liver sinusoidal endothelial cells and Kupffer cells. More DSPE-PEG2000/PVP/AOT stabilized particles accumulated in the liver, preferably in Kupffer cells, compared to Pluronic F127/PVP/AOT stabilized particles. The present study extends the understanding of PEG-ylation and "stealth" behaviour to also include nanocrystals.
authors.affiliation: AstraZeneca R&D Gothenburg, S-431 83 Mölndal, Sweden. Electronic address: carl-gustav.sigfridsson@astrazeneca.com.
authors.forename: Kalle
authors.initials: K
authors.lastname: Sigfridsson
authors.affiliation: AstraZeneca R&D Gothenburg, S-431 83 Mölndal, Sweden.
authors.forename: Pia
authors.initials: P
authors.lastname: Skantze
authors.affiliation: AstraZeneca R&D Gothenburg, S-431 83 Mölndal, Sweden.
authors.forename: Urban
authors.initials: U
authors.lastname: Skantze
authors.affiliation: AstraZeneca R&D Gothenburg, S-431 83 Mölndal, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Svensson
authors.affiliation: AstraZeneca R&D Gothenburg, S-431 83 Mölndal, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Löfgren
authors.affiliation: AstraZeneca R&D Gothenburg, S-431 83 Mölndal, Sweden.
authors.forename: Pär
authors.initials: P
authors.lastname: Nordell
authors.affiliation: AstraZeneca R&D Gothenburg, S-431 83 Mölndal, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Michaëlsson
authors.affiliation: D'Liver AS, 9294 Tromsø, Norway; Vascular Biology Research Group, Department of Medical Biology, University of Tromsø, Tromsø, Norway.
authors.forename: Bård
authors.initials: B
authors.lastname: Smedsrød
authors.affiliation: D'Liver AS, 9294 Tromsø, Norway.
authors.forename: Britt
authors.initials: B
authors.lastname: Fuglesteg
authors.affiliation: D'Liver AS, 9294 Tromsø, Norway.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Elvevold
authors.affiliation: AstraZeneca R&D Gothenburg, S-431 83 Mölndal, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Lindfors
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D010714:Phosphatidylethanolamines; D011092:Polyethylene Glycols
keywords: Biodistribution; DSPE-PEG; Liver cells; Nanosuspension; Pluronic; Poloxamer; Surface stabilized