Preclinical toxicology of biovectorTM nanoparticles: part II, local tolerance, genetic toxicology and pharmacokinetics
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文摘
BiovectorTM nanoparticles are a family of cross-linked polysaccharide nanoparticles surrounded by a lipid layer, developed as a vehicle for drug delivery. The local tolerance, genetic toxicology and pharmacokinetics of a cationic BiovectorTM with high charge density have been evaluated prior to human healthy volunteer studies by the intranasal route. The local tolerance was studied following twice daily intranasal administration to New Zealand rabbits over a period of seven days. The local tolerance was good and there were no treatment-related clinical or histopathology findings. The potential mutagenicity of BiovectorTM nanoparticles was studied in the Ames test and the mouse micronucleus test: negative results were obtained in both studies. The plasma kinetics and tissue distribution of radiolabelled BiovectorTM nanoparticles was studied after intranasal administration to rats. Systemic absorption was low, and the BiovectorTM nanoparticles were retained on the nasal turbinates. These findings were confirmed by whole body autoradiography. In a further study, the excretion balance was evaluated after intranasal and intravenous administration of radiolabelled BiovectorTM to rats. This study confirmed that systemic absorption is very low after intranasal administration, while after intravenous administration the elimination of the radioactive dose was slow and most radioactivity was excreted via the kidneys in the urine. The long residence time in the nasal turbinates and low systemic absorption constitute a favourable pharmacokinetic profile for administration to the nasal mucosae. The local tolerance and mutagenicity results indicate a good safety profile for the BiovectorTM nanoparticles.