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Spray drying siRNA-lipid nanoparticles for dry powder pulmonary delivery. | LitMetric

Spray drying siRNA-lipid nanoparticles for dry powder pulmonary delivery.

J Control Release

Department of Pharmacy, Pharmaceutical Technology and Biopharmacy, Ludwig-Maximilians Universität München, 81377 Munich, Germany; Institute of Lung Health and Immunity (LHI) and Comprehensive Pneumology Center (CPC) with the CPC-M bioArchive, Helmholtz Munich, Member of the German Center for Lung Research (DZL), Munich, Germany. Electronic address:

Published: November 2022

AI Article Synopsis

  • * Researchers engineered spray-dried lipid nanoparticle (LNP) powders to effectively deliver siRNA, aiming for specific particle sizes, low moisture levels, and minimal RNA loss while maintaining bioactivity.
  • * The results show that these spray-dried LNPs penetrate lung mucus and achieve over 90% protein downregulation and around 50% gene silencing in human lung slices, confirming their effectiveness and safety for potential therapeutic use.

Article Abstract

While all the siRNA drugs on the market target the liver, the lungs offer a variety of currently undruggable targets which could potentially be treated with RNA therapeutics. Hence, local, pulmonary delivery of RNA nanoparticles could finally enable delivery beyond the liver. The administration of RNA drugs via dry powder inhalers offers many advantages related to physical, chemical and microbial stability of RNA and nanosuspensions. The present study was therefore designed to test the feasibility of engineering spray dried lipid nanoparticle (LNP) powders. Spray drying was performed using 5% lactose solution (m/V), and the targets were set to obtain nanoparticle sizes after redispersion of spray-dried powders around 150 nm, a residual moisture level below 5%, and RNA loss below 15% at maintained RNA bioactivity. The LNPs consisted of an ionizable cationic lipid which is a sulfur-containing analog of DLin-MC3-DMA, a helper lipid, cholesterol, and PEG-DMG encapsulating siRNA. Prior to the spray drying, the latter process was simulated with a novel dual emission fluorescence spectroscopy method to preselect the highest possible drying temperature and excipient solution maintaining LNP integrity and stability. Through characterization of physicochemical and aerodynamic properties of the spray dried powders, administration criteria for delivery to the lower respiratory tract were fulfilled. Spray dried LNPs penetrated the lung mucus layer and maintained bioactivity for >90% protein downregulation with a confirmed safety profile in a lung adenocarcinoma cell line. Additionally, the spray dried LNPs successfully achieved up to 50% gene silencing of the house keeping gene GAPDH in ex vivo human precision-cut lung slices at without increasing cytokine levels. This study verifies the successful spray drying procedure of LNP-siRNA systems maintaining their integrity and mediating strong gene silencing efficiency on mRNA and protein levels both in vitro and ex vivo. The successful spray drying procedure of LNP-siRNA formulations in 5% lactose solution creates a novel siRNA-based therapy option to target respiratory diseases such as lung cancer, asthma, COPD, cystic fibrosis and viral infections.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7613708PMC
http://dx.doi.org/10.1016/j.jconrel.2022.09.021DOI Listing

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