PURPOSE: To evaluate the pulmonary distribution of CGP69846A (ISIS 5132), a phosphorothioate oligonucleotide, following intra-tracheal (i.t.) instillation into Brown-Norway rats. METHODS: The pharmacokinetic profile of [3H]-CGP69846A was investigated following i.t. instillation into both naive and inflamed airways of Brown-Norway rats. The cellular distribution was determined using autoradiography, immunohistochemistry and flow cytometry/fluorescence microscopy, in inflamed airways. RESULTS: CGP69846A displayed a dose-dependent lung retention following i.t. administration which was unaffected by local inflammation. Autoradiography and immunohistochemistry showed distribution to alveolar macrophages, eosinophils, bronchial and tracheal epithelium and alveolar cells. Studies with [FITC]-CGP69846A demonstrated a preferential association of oligonucleotide with leukocytes in bronchial lavage fluid of: macrophages > eosinophils = neutrophils >> lymphocytes. CONCLUSIONS: The dose-dependency of lung retention together with cell-specific uptake suggests that the lung can be used as a local target for antisense molecules with potentially minimal systemic effects. Furthermore, the preferential targeting of macrophages and the airway epithelium by oligonucleotides may represent rational cellular targets for antisense therapeutics.
PURPOSE: To evaluate the pulmonary distribution of CGP69846A (ISIS 5132), a phosphorothioate oligonucleotide, following intra-tracheal (i.t.) instillation into Brown-Norway rats. METHODS: The pharmacokinetic profile of [3H]-CGP69846A was investigated following i.t. instillation into both naive and inflamed airways of Brown-Norway rats. The cellular distribution was determined using autoradiography, immunohistochemistry and flow cytometry/fluorescence microscopy, in inflamed airways. RESULTS: CGP69846A displayed a dose-dependent lung retention following i.t. administration which was unaffected by local inflammation. Autoradiography and immunohistochemistry showed distribution to alveolar macrophages, eosinophils, bronchial and tracheal epithelium and alveolar cells. Studies with [FITC]-CGP69846A demonstrated a preferential association of oligonucleotide with leukocytes in bronchial lavage fluid of: macrophages > eosinophils = neutrophils >> lymphocytes. CONCLUSIONS: The dose-dependency of lung retention together with cell-specific uptake suggests that the lung can be used as a local target for antisense molecules with potentially minimal systemic effects. Furthermore, the preferential targeting of macrophages and the airway epithelium by oligonucleotides may represent rational cellular targets for antisense therapeutics.
Authors: G Hartmann; A Krug; M Bidlingmaier; U Hacker; A Eigler; R Albrecht; C J Strasburger; S Endres Journal: J Pharmacol Exp Ther Date: 1998-05 Impact factor: 4.030
Authors: S T Crooke; M J Graham; J E Zuckerman; D Brooks; B S Conklin; L L Cummins; M J Greig; C J Guinosso; D Kornbrust; M Manoharan; H M Sasmor; T Schleich; K L Tivel; R H Griffey Journal: J Pharmacol Exp Ther Date: 1996-05 Impact factor: 4.030
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