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Article: Effective mRNA pulmonary delivery by dry powder formulation of PEGylated synthetic KL4 peptide

TitleEffective mRNA pulmonary delivery by dry powder formulation of PEGylated synthetic KL4 peptide
Authors
KeywordsInhalationm
RNA transfection
PEGylation
Peptide
Spray drying
Issue Date2019
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jconrel
Citation
Journal of Controlled Release, 2019, v. 314, p. 102-115 How to Cite?
AbstractPulmonary delivery of messenger RNA (mRNA) has considerable potential as therapy or vaccine for a range of lung diseases. Inhaled dry powder formulation of mRNA is particularly attractive as it has superior stability and dry powder inhaler is relatively easy to use. A safe and effective mRNA delivery vector as well as a suitable particle engineering method are required to produce a dry powder formulation that is respirable and mediates robust transfection in the lung. Here, we introduce a novel RNA delivery vector, PEG12KL4, in which the synthetic cationic KL4 peptide is attached to a monodisperse linear PEG of 12-mers. The PEG12KL4 formed nano-sized complexes with mRNA at 10:1 ratio (w/w) and mediated effective transfection on human lung epithelial cells. PEG12KL4/mRNA complexes were successfully formulated into dry powder by spray drying (SD) and spray freeze drying (SFD) techniques. Both SD and SFD powder exhibited satisfactory aerosol properties for inhalation. More importantly, the biological activity of the PEG12KL4 /mRNA complexes were successfully preserved after drying. Using luciferase mRNA, the intratracheal administration of the liquid or powder aerosol of PEG12KL4 /mRNA complexes at a dose of 5 μg mRNA resulted in luciferase expression in the deep lung region of mice 24 h post-transfection. The transfection efficiency was superior to naked mRNA or lipoplexes (Lipofectamine 2000), in which luciferase expression was weaker and restricted to the tracheal region only. There was no sign of inflammatory response or toxicity of the PEG12KL4 /mRNA complexes after single intratracheal administration. Overall, PEG12KL4 is an excellent mRNA transfection agent for pulmonary delivery. This is also the first study that successfully demonstrates the preparation of inhalable dry powder mRNA formulations with in vivo transfection efficiency, showing the great promise of PEG12KL4 peptide as a mRNA delivery vector candidate for clinical applications. © 2019 The Authors
Persistent Identifierhttp://hdl.handle.net/10722/280093
ISSN
2019 Impact Factor: 7.727
2015 SCImago Journal Rankings: 2.827
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorQiu, Y-
dc.contributor.authorMan, CH-
dc.contributor.authorLiao, Q-
dc.contributor.authorKung, KLK-
dc.contributor.authorChow, YT-
dc.contributor.authorLam, JKW-
dc.date.accessioned2020-01-06T02:00:51Z-
dc.date.available2020-01-06T02:00:51Z-
dc.date.issued2019-
dc.identifier.citationJournal of Controlled Release, 2019, v. 314, p. 102-115-
dc.identifier.issn0168-3659-
dc.identifier.urihttp://hdl.handle.net/10722/280093-
dc.description.abstractPulmonary delivery of messenger RNA (mRNA) has considerable potential as therapy or vaccine for a range of lung diseases. Inhaled dry powder formulation of mRNA is particularly attractive as it has superior stability and dry powder inhaler is relatively easy to use. A safe and effective mRNA delivery vector as well as a suitable particle engineering method are required to produce a dry powder formulation that is respirable and mediates robust transfection in the lung. Here, we introduce a novel RNA delivery vector, PEG12KL4, in which the synthetic cationic KL4 peptide is attached to a monodisperse linear PEG of 12-mers. The PEG12KL4 formed nano-sized complexes with mRNA at 10:1 ratio (w/w) and mediated effective transfection on human lung epithelial cells. PEG12KL4/mRNA complexes were successfully formulated into dry powder by spray drying (SD) and spray freeze drying (SFD) techniques. Both SD and SFD powder exhibited satisfactory aerosol properties for inhalation. More importantly, the biological activity of the PEG12KL4 /mRNA complexes were successfully preserved after drying. Using luciferase mRNA, the intratracheal administration of the liquid or powder aerosol of PEG12KL4 /mRNA complexes at a dose of 5 μg mRNA resulted in luciferase expression in the deep lung region of mice 24 h post-transfection. The transfection efficiency was superior to naked mRNA or lipoplexes (Lipofectamine 2000), in which luciferase expression was weaker and restricted to the tracheal region only. There was no sign of inflammatory response or toxicity of the PEG12KL4 /mRNA complexes after single intratracheal administration. Overall, PEG12KL4 is an excellent mRNA transfection agent for pulmonary delivery. This is also the first study that successfully demonstrates the preparation of inhalable dry powder mRNA formulations with in vivo transfection efficiency, showing the great promise of PEG12KL4 peptide as a mRNA delivery vector candidate for clinical applications. © 2019 The Authors-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jconrel-
dc.relation.ispartofJournal of Controlled Release-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectInhalationm-
dc.subjectRNA transfection-
dc.subjectPEGylation-
dc.subjectPeptide-
dc.subjectSpray drying-
dc.titleEffective mRNA pulmonary delivery by dry powder formulation of PEGylated synthetic KL4 peptide-
dc.typeArticle-
dc.identifier.emailChow, YT: mytchow@hku.hk-
dc.identifier.emailLam, JKW: jkwlam@hku.hk-
dc.identifier.authorityLam, JKW=rp01346-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.jconrel.2019.10.026-
dc.identifier.pmid31629037-
dc.identifier.scopuseid_2-s2.0-85074101282-
dc.identifier.hkuros308910-
dc.identifier.volume314-
dc.identifier.spage102-
dc.identifier.epage115-
dc.identifier.isiWOS:000499615300010-
dc.publisher.placeNetherlands-

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