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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Abstract | [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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AbstractList | 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 CO
-assisted spray drying can enable efficient RNA interference therapy of pulmonary diseases including lung cancer. 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 CO 2 -assisted spray drying can enable efficient RNA interference therapy of pulmonary diseases including lung cancer. [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. |
ArticleNumber | 119989 |
Author | Silva, A. Sofia Morton, Stephen W. Casimiro, Teresa Aguiar-Ricardo, Ana Shopsowitz, Kevin E. Dreaden, Erik C. Correa, Santiago Hammond, Paula T. |
AuthorAffiliation | d Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, United States b Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States c Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States a LAQV-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal |
AuthorAffiliation_xml | – name: a LAQV-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal – name: b Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States – name: c Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States – name: d Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, United States |
Author_xml | – sequence: 1 givenname: A. Sofia surname: Silva fullname: Silva, A. Sofia email: sofiamsilva@ua.pt organization: LAQV-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal – sequence: 2 givenname: Kevin E. surname: Shopsowitz fullname: Shopsowitz, Kevin E. organization: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, United States – sequence: 3 givenname: Santiago surname: Correa fullname: Correa, Santiago organization: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, United States – sequence: 4 givenname: Stephen W. surname: Morton fullname: Morton, Stephen W. organization: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, United States – sequence: 5 givenname: Erik C. surname: Dreaden fullname: Dreaden, Erik C. organization: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, United States – sequence: 6 givenname: Teresa surname: Casimiro fullname: Casimiro, Teresa organization: LAQV-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal – sequence: 7 givenname: Ana surname: Aguiar-Ricardo fullname: Aguiar-Ricardo, Ana email: air@fct.unl.pt organization: LAQV-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal – sequence: 8 givenname: Paula T. surname: Hammond fullname: Hammond, Paula T. email: hammond@mit.edu organization: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, United States |
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Keywords | Small interfering RNAs Supercritical carbon dioxide Layer-by-layer nanoparticles Micronized systems Pulmonary delivery |
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Notes | 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 |
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23 Rouquerol (10.1016/j.ijpharm.2020.119989_b0235) 1999 Agnoletti (10.1016/j.ijpharm.2020.119989_b0005) 2017; 120 Al-Qadi (10.1016/j.ijpharm.2020.119989_b0015) 2012; 157 Hartmann (10.1016/j.ijpharm.2020.119989_b0135) 2013; 168 Ortiz (10.1016/j.ijpharm.2020.119989_b0210) 2015; 16 Correa (10.1016/j.ijpharm.2020.119989_b0070) 2015; 240 Moreira (10.1016/j.ijpharm.2020.119989_b0180) 2014; 88 Qu (10.1016/j.ijpharm.2020.119989_b0220) 2017; 24 Taratula (10.1016/j.ijpharm.2020.119989_b0265) 2011; 19 Chung (10.1016/j.ijpharm.2020.119989_b0050) 2017; 114 Feldmann (10.1016/j.ijpharm.2020.119989_b0120) 2015; 6 De Backer (10.1016/j.ijpharm.2020.119989_b0085) 2015; 220 Chow (10.1016/j.ijpharm.2020.119989_b0045) 2017; 530 Naikwade (10.1016/j.ijpharm.2020.119989_b0195) 2009; 10 10.1016/j.ijpharm.2020.119989_b0020 Council of Europe (10.1016/j.ijpharm.2020.119989_b0080) 2010 Lam (10.1016/j.ijpharm.2020.119989_b0160) 2012; 64 Choi (10.1016/j.ijpharm.2020.119989_b0040) 2010; 31 Xue (10.1016/j.ijpharm.2020.119989_b0315) 2014; 24 Wang (10.1016/j.ijpharm.2020.119989_b0290) 2014; 7 Caruso (10.1016/j.ijpharm.2020.119989_b0035) 2012; 41 Costa (10.1016/j.ijpharm.2020.119989_b0075) 2018; 63 Correa (10.1016/j.ijpharm.2020.119989_b0065) 2016; 26 10.1016/j.ijpharm.2020.119989_b0095 Okuda (10.1016/j.ijpharm.2020.119989_b0200) 2013; 36 Pai (10.1016/j.ijpharm.2020.119989_b0215) 2015; 28 Sharma (10.1016/j.ijpharm.2020.119989_b0240) 2013; 455 Xu (10.1016/j.ijpharm.2020.119989_b0300) 2015; 5 Aguiar-Ricardo (10.1016/j.ijpharm.2020.119989_b0010) 2019 Connor (10.1016/j.ijpharm.2020.119989_b0060) 2005; 1 |
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•siRNA nanovehicles were micronized using supercritical CO2-assisted spray drying.•The siRNA integrity was preserved through the... Small interfering RNA (siRNA) therapy has significant potential for the treatment of myriad diseases, including cancer. While intravenous routes of delivery... |
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SubjectTerms | Layer-by-layer nanoparticles Micronized systems Pulmonary delivery Small interfering RNAs Supercritical carbon dioxide |
Title | Rational design of multistage drug delivery vehicles for pulmonary RNA interference therapy |
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