Feasibility, distribution, and efficacy of an inhaled oligonucleotide mimic of miR-29 for pulmonary fibrosis induced by bleomycin in rats
| Autor: | Rusty L. Montgomery, Linda A Pestano, Catherine Nicholas, Guoying Yu, Farida Ahangari, Naftali Kaminski, Jacob D. McDonald, Philip J. Kuehl, Jeremy Brower, Christina Dalby, Jose D. Herazo-Maya, Brent A Dickinson, Corrie L. Gallant-Behm |
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| Rok vydání: | 2017 |
| Předmět: |
Biodistribution
Lung Inhalation business.industry Pharmacology medicine.disease Bleomycin 03 medical and health sciences Nebulizer chemistry.chemical_compound 0302 clinical medicine medicine.anatomical_structure 030228 respiratory system chemistry Fibrosis Pulmonary fibrosis Medicine Distribution (pharmacology) 030212 general & internal medicine business |
| Zdroj: | Mechanisms of Lung Injury and Repair. |
| Popis: | miRNA-29 targets multiple profibrotic molecules and is down-regulated during organ fibrosis, including IPF. Previously, we showed a synthetic, chemically stabilized oligonucleotide mimic of miR-29b could repress collagen expression and abrogate pulmonary fibrosis in the bleomycin mouse model when administered I.V. Preliminary studies using a Scireq inExpose inhalation system yielded positive results with miR-29 mimic in bleomycin-treated mice. Here, we sought to determine the feasibility of nebulizing the miR-29 mimic and to assess the biodistribution properties via nose-only inhalation in rats using a more sophisticated system. miR-29 mimic aerosols were generated with an Aeroneb Solo nebulizer, analyzed by HPLC for compound integrity, and connected to a nose-only rat inhalation system. Rats were challenged with bleomycin at day 0 and received a single dose of miR-29 mimic at target doses of 0.5 or 5 mg/kg by nose-only inhalation and were sacrificed 6, 24, or 48 hours later for analysis. Using a dual probe hybridization assay, distribution to the lung was robust and dose-dependent, with significant clearance at 48 hours. Minimal compound was detected in the kidney (4.9 pmol/g) and plasma (46 pmol/mL) at 6 hours in the 5 mg/kg group only, with no detection observed in heart, liver, or spleen. These data demonstrate the feasibility of nebulizing and delivering a mimic of miR-29 by nose-only inhalation, with robust and restricted delivery to the lung. We are currently assessing the efficacy of aerosolized miR-29 mimic in bleomycin-induced pulmonary fibrosis in rats using multiple doses and schedules; the data will be presented at the congress. |
| Databáze: | OpenAIRE |
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