title: Gemcitabine aerosol: in vitro antitumor activity and deposition imaging for preclinical safety assessment in baboons.
abstract: OBJECTIVE
  To characterize gemcitabine aerosol, its in vitro activity against lung cancer cells, its deposition, and tolerance in a non-human primate model.
  
  
  METHODS
  In vitro cytotoxicity of nebulized gemcitabine against NCI-H460 and A549 lung cancer cells was tested using a growth inhibition assay and compared with non-nebulized gemcitabine. The (99m)Tc-DTPA-radiolabeled gemcitabine aerosol was characterized by cascade impaction and the gemcitabine mass/(99m)Tc activity relationship was established for further quantitative nuclear imaging. Nine weekly inhalations at a target dose of 1 mg/kg body weight of gemcitabine were performed in three baboons using dynamic scintigraphic acquisitions for continuous monitoring of gemcitabine delivery during inhalation. Gemcitabine plasma concentrations were measured during the first inhalation.
  
  
  RESULTS
  Growth inhibition assays for both NCI-H460 and A549 cells did not differ between nebulized and non-nebulized gemcitabine. Aerosol characterization showed a particle mass median aerodynamic diameter of 3.7+/-0.8 microm and a linear relationship between gemcitabine mass (y) and (99m)Tc activity (x) (y=0.82x - 10(-5), R (2)=0.88). No toxicity was observed after nine weekly inhalations of a mean dose of gemcitabine of 11.1 mg (88% of the target dose) as assessed from scintigraphic data. A dose-dependent peak plasma concentration of gemcitabine (20-74 ng/ml) was observed by the tenth minute of inhalation.
  
  
  CONCLUSIONS
  We have characterized a gemcitabine aerosol suitable for intrathoracic airway deposition and demonstrated that jet nebulization does not alter the cytotoxic properties of the drug. In a primate model, we have developed a scintigraphic procedure for the monitoring of aerosol deposition, and we have demonstrated the safety of nine weekly aerosol administrations of gemcitabine.
authors.affiliation: Groupe de pneumologie Faculté de Médecine, INSERM, U618, IFR135, 37032 Tours, France. frgagnadoux@chu-angers.fr
authors.forename: Frédéric
authors.initials: F
authors.lastname: Gagnadoux
authors.forename: Valérie
authors.initials: V
authors.lastname: Leblond
authors.forename: Laurent
authors.initials: L
authors.lastname: Vecellio
authors.forename: José
authors.initials: J
authors.lastname: Hureaux
authors.forename: Alain
authors.initials: A
authors.lastname: Le Pape
authors.forename: Michèle
authors.initials: M
authors.lastname: Boisdron-Celle
authors.forename: Jérome
authors.initials: J
authors.lastname: Montharu
authors.forename: Caroline
authors.initials: C
authors.lastname: Majoral
authors.forename: Joseph
authors.initials: J
authors.lastname: Fournier
authors.forename: Thierry
authors.initials: T
authors.lastname: Urban
authors.forename: Patrice
authors.initials: P
authors.lastname: Diot
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Racineux
authors.forename: Etienne
authors.initials: E
authors.lastname: Lemarié
mesh_terms: D000336:Aerosols; D000818:Animals; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D005260:Female; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D023421:Models, Animal; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy*; D010215:Papio; D011877:Radionuclide Imaging; D000093542:Gemcitabine
chemical_list: D000336:Aerosols; D003841:Deoxycytidine; D000093542:Gemcitabine