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Beyerle, A.* ; Braun, A. ; Merkel, O.* ; Koch, F.* ; Kissel, T.* ; Stöger, T.

Comparative in vivo study of poly(ethylene imine)/siRNA complexes for pulmonary delivery in mice.

J. Control. Release 151, 51-56 (2011)
DOI
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Pulmonary siRNA delivery offers a new way to treat various lung diseases. Poly(ethylene imines) (PEIs) are promising cationic nanocarriers and various modifications are still under investigations to improve their cytotoxicity and efficacy for siRNA delivery. In this study, we analyzed two different types of PEI-based nanocomplexes in mice after intratracheal administration regarding their toxicity and efficacy in the lungs. Ubiquitously enhanced green fluorescent protein (EGFP) expressing transgenic and BALB/c mice were intratracheally instilled with 35μg siRNA complexed with the different types of PEI nanocarriers. Lung toxicity and inflammation were investigated after 24h, 3d and 7d treatment and knockdown of EGFP expression was analyzed by flow cytometry and fluorescence microscopy five days post instillation. Three different polyplexes caused more than 60% knockdown of EGFP expression, but only the fatty acid modified low molecular weight PEI 8.3kDa (C16-C18-EO25)1.4 specifically reduced EGFP expression in CD45+ leucocytes (25±12%) and CD11b-/CD11c+ lung macrophages (36±14%). Hydrophobic and hydrophilic PEG modifications on PEI caused severe inflammatory response and elevated levels of IgM in broncho-alveolar fluid (BALF). Thus, the PEG modification reduced cytotoxicity, but elevated the immune response and proinflammatory effects. Further investigations of the proinflammatory and immunomodulatory effects of the PEI-modified carriers are necessary to clarify the highly unspecific knockdown effects in the lung in more detail. Nevertheless, the more hydrophobic modification of PEI based non-viral vector system appeared to be a promising approach for improved siRNA therapeutics offering successful pulmonary siRNA delivery.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter siRNA delivery; EGFP; Intratracheal instillation; PEI; Polyplexes
ISSN (print) / ISBN 0168-3659
e-ISSN 1873-4995
Quellenangaben Band: 151, Heft: 1, Seiten: 51-56 Artikelnummer: , Supplement: ,
Verlag Elsevier
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Lung Biology (ILBD)
CCG Environmental Dermatology and Allergology (ILBD-KAU)
Institute of Epidemiology (EPI)