Journal
PHARMACEUTICS
Volume 12, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/pharmaceutics12111042
Keywords
gene therapy; mRNA therapeutics; lipid nanoparticles; pulmonary delivery; aerosolization
Categories
Funding
- NIH National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health [R01HL138251]
- College of Pharmacy, University of Texas at Austin
- University Graduate Continuing Fellowship, The Graduate School, University of Texas at Austin
- Cystic Fibrosis Foundation [LEAL19XX0, GHOSH19XX0]
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Messenger RNA is a class of promising nucleic acid therapeutics to treat a variety of diseases, including genetic diseases. The development of a stable and efficacious mRNA pulmonary delivery system would enable high therapeutic concentrations locally in the lungs to improve efficacy and limit potential toxicities. In this study, we employed a Design of Experiments (DOE) strategy to screen a library of lipid nanoparticle compositions to identify formulations possessing high potency both before and after aerosolization. Lipid nanoparticles (LNPs) showed stable physicochemical properties for at least 14 days of storage at 4 degrees C, and most formulations exhibited high encapsulation efficiencies greater than 80%. Generally, upon nebulization, LNP formulations showed increased particle size and decreased encapsulation efficiencies. An increasing molar ratio of poly-(ethylene) glycol (PEG)-lipid significantly decreased size but also intracellular protein expression of mRNA. We identified four formulations possessing higher intracellular protein expression ability in vitro even after aerosolization which were then assessed in in vivo studies. It was found that luciferase protein was predominately expressed in the mouse lung for the four lead formulations before and after nebulization. This study demonstrated that LNPs hold promise to be applied for aerosolization-mediated pulmonary mRNA delivery.
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