The effects of oil-in-water nanoemulsion polyethylene glycol surface density on intracellular stability, pharmacokinetics, and biodistribution in tumor bearing mice.

ABSTRACT

PURPOSE: Lipid-based nanoparticles are extensively studied for drug delivery. These nanoparticles are often surface-coated with polyethylene glycol (PEG) to improve their biodistribution. Until now, the effects of varying PEG surface density have been studied in a narrow and low range. Here, the effects of high and a broad range of PEG surface densities on the in vivo performance of lipid-based nanoparticles were studied. METHODS: Oil-in-water nanoemulsions were prepared with PEG surface densities of 5-50 mol%. Confocal microscopy was used to assess intracellular disintegration in vitro. In vivo pharmacokinetics and biodistribution in tumor bearing mice were studied using a small animal optical imager. RESULTS: PEG surface density did not affect intracellular nanoemulsion stability. Surprisingly, circulation half-lives decreased with increasing PEG surface density. A plausible explanation was that nanoemulsion with high (50 mol%) PEG surface density activated the complement in a whole blood assay, whereas nanoemulsion with low (5 mol%) PEG density did not. In vivo, nanoemulsion with low PEG surface density was mostly confined to the tumor and organs of the mononuclear phagocyte system, whereas nanoemulsion with high PEG density accumulated throughout the mouse. CONCLUSIONS: Optimal PEG surface density of lipid-based nanoparticles for tumor targeting was found to be below 10 mol%.