Rational design of multistage drug delivery vehicles for pulmonary RNA interference therapy
[Display omitted] •siRNA nanovehicles were micronized using supercritical CO2-assisted spray drying.•The siRNA integrity was preserved through the micronization process.•The ultrafine dry powders showed aerodynamic diameters of 3.5 μm and FPF above 40%•The micronized siRNA powders achieved 90% of si...
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Published in | International journal of pharmaceutics Vol. 591; p. 119989 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Netherlands
Elsevier B.V
15.12.2020
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Subjects | |
Online Access | Get full text |
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Summary: | [Display omitted]
•siRNA nanovehicles were micronized using supercritical CO2-assisted spray drying.•The siRNA integrity was preserved through the micronization process.•The ultrafine dry powders showed aerodynamic diameters of 3.5 μm and FPF above 40%•The micronized siRNA powders achieved 90% of silencing for the mutant KRAS gene.•Alveolar in vivo biodistribution was achieved in healthy mice following inhalation.
Small interfering RNA (siRNA) therapy has significant potential for the treatment of myriad diseases, including cancer. While intravenous routes of delivery have been found to be effective for efficient targeting to the liver, achieving high accumulations selectively in other organs, including lung tissues, can be a challenge. We demonstrate the rational design and engineering of a layer-by-layer (LbL) nanoparticle-containing aerosol that is able to achieve efficient, multistage delivery of siRNA in vitro. For the purpose, LbL nanoparticles were, for the first time, encapsulated in composite porous micro scale particles using a supercritical CO2-assisted spray drying (SASD) apparatus using chitosan as an excipient. Such particles exhibited aerodynamic properties highly favorable for pulmonary administration, and effective silencing of mutant KRAS in lung cancer cells derived from tumors of a non-small cell lung cancer (NSCLC) autochthonous model. Furthermore, efficient alveolar accumulation following inhalation in healthy mice was also observed, corroborating in vitro aerodynamic results, and opening new perspectives for further studies of effective lung therapies These results show that multistage aerosols assembled by supercritical CO2-assisted spray drying can enable efficient RNA interference therapy of pulmonary diseases including lung cancer. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current affiliation: Faculty of Medicine, University of British Columbia, BC V1Y 1T3, Canada Current affiliation: Department of Materials Science and Engineering, Stanford University, 496 Lomita Mall, Stanford, CA 94305, USA Current affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, United States. Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, 30332, United States. Current affiliation: CICECO, Department of Chemistry, University of Aveiro, 3810193, Aveiro, Portugal |
ISSN: | 0378-5173 1873-3476 |
DOI: | 10.1016/j.ijpharm.2020.119989 |