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Kumar, P. ; Chakraborty, A. ; Richter, E. ; Yang, L. ; Schröppel, A. ; Mergault, C.* ; Rothkirch Née Knüppel, L.* ; Jaschinski, F.* ; Blayac, M. ; Vanbever, R.* ; Plantier, L.* ; Heuzé-Vourch, N.* ; Schmid, O.

Microliter-scale in vitro aerosol-cell delivery of inhalable antisense oligonucleotide (ASO) induces “burst-like” pharmacokinetics.

International Journal of Pharmaceutics: X 12:100588 (2026)
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Unlike traditional submerged cell cultures, nebulized drug delivery to air-liquid interface (ALI)-cultured lung cells provides a clinically relevant route for in vitro testing of inhalable drugs. Current nebulizer systems deliver non-physiologically large drug volumes. Here, we introduce the Cloud MAX technology, characterize its accuracy of dosimetry, and apply it to toxicity, efficacy, and biokinetics or permeability testing of a locked nucleic acid-modified antisense oligonucleotide (ASO). On average the Cloud MAX delivers 44% of 3–20 μL aerosolized liquid to ALI-cultured cells, the coefficient of variation (CV) of repeated drug dosing is '11%-rel. and as little as 1 μL of drug/insert (=0.25 μL/cm2) can be delivered to ALI-cultured cells. As proof of concept for dose-controlled in vitro drug testing, we demonstrated target engagement of a LIM and Calponin Homology domain 1 (LIMCH1)-specific ASO in primary lung fibroblasts from Idiopathic Pulmonary Fibrosis (IPF) patients “shielded” by an A549 alveolar epithelial layer mimicking inhalation therapy. LIMCH1-ASO was effective in LIMCH1-silencing even at the lowest dose (0.64 nmol/cm2). Nebulization did neither impair LIMCH1-ASO efficacy nor induce cytotoxicity for the highest tested dose (3.21 nmol/cm2). The permeability (biokinetics) of nebulized ASO through the A549 cell barrier was 14-fold faster (“burst-like”) than for larger volume (pipetted) ASO application. Computational modeling revealed that this well-known “burst-like” pharmaco−/biokinetics profile is due to small-volume drug application, not due to nebulizer-induced changes on barrier tightness (apparent permeability P app ). Thus, the Cloud MAX is a substance-efficient platform for in vitro pharmacokinetics/−dynamics testing of inhalable drugs for targeted pulmonary therapy.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cloud Max Technology ; Dosimetry ; Idiopathic Pulmonary Fibrosis (ipf) ; Limch1 Gene Silencing ; Precision Aerosol-cell Delivery ; Primary Human Lung Fibroblasts
e-ISSN 2590-1567
Zeitschrift International Journal of Pharmaceutics: X
Quellenangaben Band: 12, Heft: , Seiten: , Artikelnummer: 100588 Supplement: ,
Verlag Elsevier
Institut(e) Institute of Lung Health and Immunity (LHI)