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In vitro and ex vivo toxicological testing of sildenafil-loaded solid lipid nanoparticles

: Paranjpe, M.; Neuhaus, V.; Finke, J.H.; Richter, C.; Gothsch, T.; Kwade, A.; Büttgenbach, S.; Braun, A.; Müller-Goymann, C.C.


Inhalation Toxicology 25 (2013), No.9, pp.536-543
ISSN: 0895-8378
ISSN: 1091-7691
Journal Article
Fraunhofer ITEM ()
lung toxicity; heart toxicity; microchannel homogenization; sildenafil; solid lipid nanoparticle

The aim of this study was to investigate the potential cytotoxicity of solid lipid nanoparticles (SLN) loaded with sildenafil. The SLNs were tested as a new drug delivery system (DDS) for the inhalable treatment of pulmonary hypertension in human lungs. Solubility of sildenafil in SLN lipid matrix (30:70 phospholipid: triglyceride) was determined to 1% sildenafil base and 0.1% sildenafil citrate, respectively. Sildenafil-loaded SLN with particle size of approximately 180nm and monomodal particle size distribution were successfully manufactured using a novel microchannel homogenization method and were stable up to three months. Sildenafil-loaded SLN were then used in in vitro and ex vivo models representing lung and heart tissue. For in vitro models, human alveolar epithelial cell line (A459) and mouse heart endothelium cell line (MHEC5-T) were used. For ex vivo models, rat precision cut lung slices (PCLS) and rat heart slices (PCHS) were used. All the models were treated with plain SLN and sildenafil-loaded SLN in a concentration range of 0-5000 mu g/ml of lipid matrix. The toxicity was evaluated in vitro and ex vivo by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Median lethal dose 50% (LD50) values for A549 cells and PCLS were found to be in the range of 1200-1900 mu g/ml while for MHEC5-T cells and precision cut heart slices values were found between 1500 and 2800 mu g/ml. PCHS showed slightly higher LD50 values in comparison to PCLS. Considering the toxicological aspects, sildenafil-loaded SLN could have potential in the treatment of pulmonary hypertension via inhalation route.