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A toxicological evaluation of inhaled solid lipid nanoparticles used as a potential drug delivery system for the lung

 
: Nassimi, M.; Schleh, C.; Lauenstein, H.D.; Hussein, R.; Hoymann, H.G.; Koch, W.; Pohlmann, G.; Krug, N.; Sewald, K.; Rittinghausen, S.; Braun, A.; Müller-Goymann, C.

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European journal of pharmaceutics and biopharmaceutics 75 (2010), No.2, pp.107-116
ISSN: 0939-6411
ISSN: 1873-3441
English
Journal Article
Fraunhofer ITEM ()
solid lipid nanoparticle; precision cut lung slice; A549; BALB/c mice; pro-inflammatory cytokines; drug delivery; cytotoxicity; inflammation

Abstract
Inhalation is a non-invasive approach for both local and systemic drug delivery. This study aimed to define the therapeutic window for solid lipid nanoparticles (SLNs) as a drug delivery system by inhalation from a toxicological point of view.
To estimate the toxic dose of SLNs in vitro, A549 cells and murine precision-cut lung slices (PCLS) were exposed to increasing concentrations of SLNs. The cytotoxic effect of SLNs on A549 cells was evaluated by MTT and NRU assays. Viability of lung tissue was determined with WST assay and by life/dead staining using calcein AM/EthD-1 for confocal microscopy (CLSM) followed by quantitative analysis with IMARIS. Inflammation was assessed by measuring chemokine KC and TNF-? levels. The in vivo effects were determined in a 16-day repeated-dose inhalation toxicity study using female BALB/c mice, which were daily exposed to different concentrations of SLN30 aerosols (1–200 ?g deposit dose). Local inflammatory effects in the respiratory tract were evaluated by determination of total protein content, LDH, chemokine KC, IL-6, and differential cell counts, performed on days 4, 8, 12, and 16 in bronchoalveolar lavage fluid. Additionally, a histopathological evaluation of toxicologically relevant organs was accomplished.
The in vitro and ex vivo dose finding experiments showed toxic effects beginning at concentrations of about 500 ?g/ml. Therefore, we used 1–200 ?g deposit doses/animal for the in vivo experiments. Even after 16 days of challenge with a 200-?g deposit dose, SLNs induced no significant signs of inflammation. We observed no consistent increase in LDH release, protein levels, or other signs of inflammation such as chemokine KC, IL-6, or neutrophilia. In contrast, the particle control (carbon black) caused inflammatory and cytotoxic effects at corresponding concentrations.
These results confirm that repeated inhalation exposure to SLN30 at concentrations lower than a 200-?g deposit dose is safe in a murine inhalation model.

: http://publica.fraunhofer.de/documents/N-134545.html