PMID- 20206256
OWN - NLM
STAT- MEDLINE
DCOM- 20100909
LR  - 20100524
IS  - 1873-3441 (Electronic)
IS  - 0939-6411 (Linking)
VI  - 75
IP  - 2
DP  - 2010 Jun
TI  - A toxicological evaluation of inhaled solid lipid nanoparticles used as a 
      potential drug delivery system for the lung.
PG  - 107-16
LID - 10.1016/j.ejpb.2010.02.014 [doi]
AB  - 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-alpha 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 microg 
      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 
      microg/ml. Therefore, we used 1-200 microg deposit doses/animal for the in vivo 
      experiments. Even after 16 days of challenge with a 200-microg 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-microg deposit dose is safe in a murine inhalation model.
CI  - Copyright 2010 Elsevier B.V. All rights reserved.
FAU - Nassimi, M
AU  - Nassimi M
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine, Department of 
      Immunology, Allergology and Immunotoxicology, Hannover, Germany.
FAU - Schleh, C
AU  - Schleh C
FAU - Lauenstein, H D
AU  - Lauenstein HD
FAU - Hussein, R
AU  - Hussein R
FAU - Hoymann, H G
AU  - Hoymann HG
FAU - Koch, W
AU  - Koch W
FAU - Pohlmann, G
AU  - Pohlmann G
FAU - Krug, N
AU  - Krug N
FAU - Sewald, K
AU  - Sewald K
FAU - Rittinghausen, S
AU  - Rittinghausen S
FAU - Braun, A
AU  - Braun A
FAU - Muller-Goymann, C
AU  - Muller-Goymann C
LA  - eng
PT  - Journal Article
DEP - 20100303
PL  - Netherlands
TA  - Eur J Pharm Biopharm
JT  - European journal of pharmaceutics and biopharmaceutics : official journal of 
      Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
JID - 9109778
RN  - 0 (Lipids)
SB  - IM
MH  - Administration, Inhalation
MH  - Animals
MH  - Bronchoalveolar Lavage Fluid
MH  - Cell Line, Tumor
MH  - Dose-Response Relationship, Drug
MH  - *Drug Delivery Systems
MH  - Female
MH  - Humans
MH  - Inflammation/chemically induced/physiopathology
MH  - Lipids/administration & dosage/chemistry/*toxicity
MH  - Lung/*drug effects/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Microscopy, Confocal
MH  - Nanoparticles/*toxicity
MH  - Time Factors
MH  - Toxicity Tests
EDAT- 2010/03/09 06:00
MHDA- 2010/09/10 06:00
CRDT- 2010/03/09 06:00
PHST- 2009/11/10 00:00 [received]
PHST- 2010/02/03 00:00 [revised]
PHST- 2010/02/27 00:00 [accepted]
PHST- 2010/03/09 06:00 [entrez]
PHST- 2010/03/09 06:00 [pubmed]
PHST- 2010/09/10 06:00 [medline]
AID - S0939-6411(10)00059-7 [pii]
AID - 10.1016/j.ejpb.2010.02.014 [doi]
PST - ppublish
SO  - Eur J Pharm Biopharm. 2010 Jun;75(2):107-16. doi: 10.1016/j.ejpb.2010.02.014. 
      Epub 2010 Mar 3.