In vitro cytotoxic and immunomodulatory profiling of low molecular weight polyethylenimines for pulmonary application.
Polyethylenimines (PEI) are potent non-viral nucleic acid delivery vehicles used for gene delivery and RNA interference (RNAi). For non-invasive pulmonary RNAi therapy the respiratory tissue is an attractive application route, but offers particularly unwanted side-effects like cytotoxicity as well as inflammatory and immune responses. In the current study, we determined the most crucial issues of pulmonary applications for two low molecular weight PEIs in comparison to the well-known lung toxic crystalline silica. Cytotoxic effects and inflammatory responses were evaluated in three murine pulmonary target cell lines, the alveolar epithelial (LA4), the alveolar macrophage (MH-S) and the macrophage-monocyte-like (RAW 264.7) cell line. For both PEIs, cytotoxicity was detected most prominently in the alveolar epithelial cells and only at high doses. Cytokine responses, in contrast were observed already at low PEI concentrations and could be divided into three groups, induced (i) by free PEI (IL-6, TNF-alpha, G-CSF), (ii) by PEI/siRNA complexes (CCL2, -5, CXCL1, -10), or (iii) unaffected by either treatment (IL-2, -4,-7, -9, and CCL3). We conclude that even for the respiratory tissue both PEIs represent powerful siRNA delivery tools with reduced cytotoxicity and minor proinflammatory potency. However, in relation to response levels observed upon crystalline silica exposures, some PEI induced proapoptotic and proinflammatory responses might not be considered completely harmless, therefore further in vivo investigations are advisable.
Beyerle
Andrea
A
Institute of Inhalation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstädter Landstrasse 1, D-85764 Neuherberg, Germany.
Höbel
Sabrina
S
Czubayko
Frank
F
Schulz
Holger
H
Kissel
Thomas
T
Aigner
Achim
A
Stoeger
Tobias
T
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D007155:Immunologic Factors / Q000737:chemistry / Q000633:toxicity*; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008970:Molecular Weight; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D011094:Polyethyleneimine / Q000737:chemistry / Q000633:toxicity*; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D034741:RNA, Small Interfering / Q000737:chemistry / Q000494:pharmacology*; D012822:Silicon Dioxide / Q000633:toxicity
D016207:Cytokines; D004337:Drug Carriers; D007155:Immunologic Factors; D034741:RNA, Small Interfering; D012822:Silicon Dioxide; D011094:Polyethyleneimine