Inhalable Dry Powders for Lung MRNA Delivery

Overview

Journal Adv Healthc Mater

Specialties Biomedical Engineering
Biotechnology

Date 2024 Oct 1

PMID 39352052

Authors

Akiva Gordon

Bowen Li

Jacob Witten

Hong Nguyen

Daniel G Anderson

Affiliations

Soon will be listed here.

Abstract

Despite great promise, application of mRNA therapeutics in the lung has proven challenging. Many groups have reported success instilling liquid mRNA formulations in animal models, but direct intratracheal administration of large liquid quantities to the human lung presents significant safety and distribution concerns. To accomplish safe and effective mRNA delivery to the lung, formulations must be prepared for dosing via inhalation. An inhaled mRNA delivery system for the lung must be both robust enough to survive inhalation conditions and potent enough to deliver mRNA upon reaching the lung. In this work dry powder lipid nanoparticle formulations are developed, using spray-freeze-drying, to produce stable, biologically active, inhalable dry powders for mRNA delivery. The final powders have suitable aerosolization properties, with mean mass aerodynamic diameter (MMAD) of 3-4 microns, and fine particle fraction (FPF) ≈40%, allowing for efficient mRNA delivery to the deep lung following inhalation. Importantly, the formulations developed here are suitable for use with different ionizable lipids. Four different ionizable lipid-based formulations are evaluated as powders, and all exhibit in vivo pulmonary mRNA delivery equal to that of instilled liquid formulations. These results lay promising groundwork for the eventual development of an inhalable mRNA dry powder therapeutic.

Citing Articles

Inhalable Dry Powders for Lung mRNA Delivery.

Gordon A, Li B, Witten J, Nguyen H, Anderson D Adv Healthc Mater. 2024; 13(29):e2400509.

PMID: 39352052 PMC: 11582499. DOI: 10.1002/adhm.202400509.

References

Rowe S, Zuckerman J, Dorgan D, Lascano J, McCoy K, Jain M . Inhaled mRNA therapy for treatment of cystic fibrosis: Interim results of a randomized, double-blind, placebo-controlled phase 1/2 clinical study. J Cyst Fibros. 2023; 22(4):656-664. PMC: 10524666. DOI: 10.1016/j.jcf.2023.04.008. View

Liang W, Chan A, Chow M, Lo F, Qiu Y, Kwok P . Spray freeze drying of small nucleic acids as inhaled powder for pulmonary delivery. Asian J Pharm Sci. 2020; 13(2):163-172. PMC: 7032260. DOI: 10.1016/j.ajps.2017.10.002. View

Elborn J . Cystic fibrosis. Lancet. 2016; 388(10059):2519-2531. DOI: 10.1016/S0140-6736(16)00576-6. View

Wu J, Wu L, Wan F, Rantanen J, Cun D, Yang M . Effect of thermal and shear stresses in the spray drying process on the stability of siRNA dry powders. Int J Pharm. 2019; 566:32-39. DOI: 10.1016/j.ijpharm.2019.05.019. View

Fahrni M, Ismail I, Refi D, Almeman A, Yaakob N, Saman K . Management of COVID-19 vaccines cold chain logistics: a scoping review. J Pharm Policy Pract. 2022; 15(1):16. PMC: 8889047. DOI: 10.1186/s40545-022-00411-5. View

Liang W, Chow M, Lau P, Zhou Q, Kwok P, Leung G . Inhalable dry powder formulations of siRNA and pH-responsive peptides with antiviral activity against H1N1 influenza virus. Mol Pharm. 2015; 12(3):910-21. DOI: 10.1021/mp500745v. View

Qiu Y, Man R, Liao Q, Kung K, Chow M, Lam J . Effective mRNA pulmonary delivery by dry powder formulation of PEGylated synthetic KL4 peptide. J Control Release. 2019; 314:102-115. DOI: 10.1016/j.jconrel.2019.10.026. View

Farbiak L, Cheng Q, Wei T, Alvarez-Benedicto E, Johnson L, Lee S . All-In-One Dendrimer-Based Lipid Nanoparticles Enable Precise HDR-Mediated Gene Editing In Vivo. Adv Mater. 2021; 33(30):e2006619. PMC: 10041668. DOI: 10.1002/adma.202006619. View

Chow M, Qiu Y, Lo F, Lin H, Chan H, Kwok P . Inhaled powder formulation of naked siRNA using spray drying technology with l-leucine as dispersion enhancer. Int J Pharm. 2017; 530(1-2):40-52. DOI: 10.1016/j.ijpharm.2017.07.013. View

10.

Jensen D, Cun D, Maltesen M, Frokjaer S, Nielsen H, Foged C . Spray drying of siRNA-containing PLGA nanoparticles intended for inhalation. J Control Release. 2009; 142(1):138-45. PMC: 7126878. DOI: 10.1016/j.jconrel.2009.10.010. View

11.

Kim J, Jozic A, Lin Y, Eygeris Y, Bloom E, Tan X . Engineering Lipid Nanoparticles for Enhanced Intracellular Delivery of mRNA through Inhalation. ACS Nano. 2022; 16(9):14792-14806. PMC: 9939008. DOI: 10.1021/acsnano.2c05647. View

12.

Miwata K, Okamoto H, Nakashima T, Ihara D, Horimasu Y, Masuda T . Intratracheal Administration of siRNA Dry Powder Targeting Vascular Endothelial Growth Factor Inhibits Lung Tumor Growth in Mice. Mol Ther Nucleic Acids. 2018; 12:698-706. PMC: 6083018. DOI: 10.1016/j.omtn.2018.07.009. View

13.

Lokugamage M, Vanover D, Beyersdorf J, Hatit M, Rotolo L, Echeverri E . Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs. Nat Biomed Eng. 2021; 5(9):1059-1068. PMC: 10197923. DOI: 10.1038/s41551-021-00786-x. View

14.

Wang J, Hanafy M, Xu H, Leal J, Zhai Y, Ghosh D . Aerosolizable siRNA-encapsulated solid lipid nanoparticles prepared by thin-film freeze-drying for potential pulmonary delivery. Int J Pharm. 2021; 596:120215. DOI: 10.1016/j.ijpharm.2021.120215. View

15.

Shetty N, Cipolla D, Park H, Zhou Q . Physical stability of dry powder inhaler formulations. Expert Opin Drug Deliv. 2019; 17(1):77-96. PMC: 6981243. DOI: 10.1080/17425247.2020.1702643. View

16.

Jensen D, Jensen L, Koocheki S, Bengtson L, Cun D, Nielsen H . Design of an inhalable dry powder formulation of DOTAP-modified PLGA nanoparticles loaded with siRNA. J Control Release. 2011; 157(1):141-8. DOI: 10.1016/j.jconrel.2011.08.011. View

17.

Patel V, Bardoliwala D, Lalani R, Patil S, Ghosh S, Javia A . Development of a dry powder for inhalation of nanoparticles codelivering cisplatin and siRNA in lung cancer. Ther Deliv. 2021; 12(9):651-670. DOI: 10.4155/tde-2020-0117. View

18.

Maier M, Jayaraman M, Matsuda S, Liu J, Barros S, Querbes W . Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. Mol Ther. 2013; 21(8):1570-8. PMC: 3734658. DOI: 10.1038/mt.2013.124. View

19.

Liang W, Chow M, Chow S, Chan H, Kwok P, Lam J . Using two-fluid nozzle for spray freeze drying to produce porous powder formulation of naked siRNA for inhalation. Int J Pharm. 2018; 552(1-2):67-75. DOI: 10.1016/j.ijpharm.2018.09.045. View

20.

Chua H, Collis G, Newbury A, Chan K, Bower G, Sly P . The influence of age on aerosol deposition in children with cystic fibrosis. Eur Respir J. 1994; 7(12):2185-91. DOI: 10.1183/09031936.94.07122185. View