MersV1, Main, Exploration, bibRecord, 000608

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

Identifieur interne : 000608 ( Main/Exploration ); précédent : 000607; suivant : 000609

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

Auteurs : Yingshan Qiu ; Rico C H. Man ; Qiuying Liao ; Keshia L K. Kung ; Michael Y T. Chow [Australie] ; Jenny K W. Lam [République populaire de Chine]

Source :

Journal of controlled release : official journal of the Controlled Release Society [ 1873-4995 ] ; 2019.

RBID : pubmed:31629037

Abstract

Pulmonary 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 5μg mRNA resulted in luciferase expression in the deep lung region of mice 24h 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.

DOI: 10.1016/j.jconrel.2019.10.026
PubMed: 31629037

Affiliations:

Le document en format XML

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<front><div type="abstract" xml:lang="en">Pulmonary 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, PEG<sub>12</sub>
KL4, in which the synthetic cationic KL4 peptide is attached to a monodisperse linear PEG of 12-mers. The PEG<sub>12</sub>
KL4 formed nano-sized complexes with mRNA at 10:1 ratio (w/w) and mediated effective transfection on human lung epithelial cells. PEG<sub>12</sub>
KL4/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 PEG<sub>12</sub>
KL4 /mRNA complexes were successfully preserved after drying. Using luciferase mRNA, the intratracheal administration of the liquid or powder aerosol of PEG<sub>12</sub>
KL4 /mRNA complexes at a dose of 5μg mRNA resulted in luciferase expression in the deep lung region of mice 24h 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 PEG<sub>12</sub>
KL4 /mRNA complexes after single intratracheal administration. Overall, PEG<sub>12</sub>
KL4 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 PEG<sub>12</sub>
KL4 peptide as a mRNA delivery vector candidate for clinical applications.</div>
</front>
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<name sortKey="Man, Rico C H" sort="Man, Rico C H" uniqKey="Man R" first="Rico C H" last="Man">Rico C H. Man</name>
<name sortKey="Qiu, Yingshan" sort="Qiu, Yingshan" uniqKey="Qiu Y" first="Yingshan" last="Qiu">Yingshan Qiu</name>
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<country name="Australie"><noRegion><name sortKey="Chow, Michael Y T" sort="Chow, Michael Y T" uniqKey="Chow M" first="Michael Y T" last="Chow">Michael Y T. Chow</name>
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Effective mRNA pulmonary delivery by dry powder formulation of PEGylated synthetic KL4 peptide.

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

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Abstract

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