Rational design of multistage drug delivery vehicles for pulmonary RNA interference therapy

Ana Sofia Silva, Kevin E. Shopsowitz, Santiago Correa, Stephen W. Morton, Erik C. Dreaden, Teresa Casimiro, Ana Aguiar-Ricardo, Paula T. Hammond

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number119989
JournalInternational Journal of Pharmaceutics
Volume591
DOIs
Publication statusPublished - 15 Dec 2020

Keywords

  • Layer-by-layer nanoparticles
  • Micronized systems
  • Pulmonary delivery
  • Small interfering RNAs
  • Supercritical carbon dioxide

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