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Gemcitabine aerosol: in vitro antitumor activity and deposition imaging for preclinical safety assessment in baboons

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Abstract

Aim: 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 99mTc-DTPA-radiolabeled gemcitabine aerosol was characterized by cascade impaction and the gemcitabine mass/99mTc 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 μm and a linear relationship between gemcitabine mass (y) and 99mTc 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.

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Acknowledgements

Emmanuelle BOLL-BATAILLE is acknowledged for her participation in growth inhibition assays.

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Authors and Affiliations

  1. Groupe de pneumologie Faculté de Médecine, INSERM, U618, IFR135, 37032, Tours, France

    Frédéric Gagnadoux, Valérie Leblond, Laurent Vecellio, Alain Le Pape, Jérome Montharu, Caroline Majoral, Joseph Fournier, Patrice Diot & Etienne Lemarié

  2. Département de Pneumologie, CHU, 4 rue Larrey, 49033, Angers, France

    Frédéric Gagnadoux, José Hureaux, Thierry Urban & Jean-Louis Racineux

  3. Biopharmconsulting-ARAIR, 37000, Tours, France

    Alain Le Pape

  4. Unité d’Oncopharmacologie-Pharmacogénétique, INSERM U564, CRLCC Paul Papin, 49033, Angers, France

    Michèle Boisdron-Celle

Authors
  1. Frédéric Gagnadoux
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  2. Valérie Leblond
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  3. Laurent Vecellio
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  4. José Hureaux
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  5. Alain Le Pape
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  6. Michèle Boisdron-Celle
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  7. Jérome Montharu
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  8. Caroline Majoral
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  9. Joseph Fournier
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  10. Thierry Urban
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  11. Patrice Diot
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  12. Jean-Louis Racineux
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  13. Etienne Lemarié
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Corresponding author

Correspondence to Frédéric Gagnadoux.

Additional information

Research supports: This study was supported by a grant from the Comité Départemental du Maine-et-Loire de la Ligue Nationale Contre le Cancer.

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Gagnadoux, F., Leblond, V., Vecellio, L. et al. Gemcitabine aerosol: in vitro antitumor activity and deposition imaging for preclinical safety assessment in baboons. Cancer Chemother Pharmacol 58, 237–244 (2006). https://doi.org/10.1007/s00280-005-0146-9

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  • DOI: https://doi.org/10.1007/s00280-005-0146-9

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