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The Effects of oil-in-Water Nanoemulsion Polyethylene Glycol Surface Density on Intracellular Stability, Pharmacokinetics, and Biodistribution in Tumor Bearing Mice

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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%.

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Abbreviations

ICA:

Intensity correlation analysis

ICQ:

Intensity correlation quotient

NE:

Nanoemulsion

PDM:

Product of differences from the mean

PEG:

Polyethylene glycol

PEG-DSPE:

1,2-disteraoyl-sn-glycerol-3-phosphoethanolamine-N-[methoxy(polyethylene-glycol)-2000]

PX (with X = 5, 10, 30, 50):

Nanoemulsion containing X mol% PEG-DSPE

SBR:

Signal to background ratio

TCC:

Total complement complex

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ACKNOWLEDGMENTS AND DISCLOSURES

We gratefully thank K. Grendstad Sæterbø for help with cell culturing and S. Eggen for help with the xenografts. The work was supported by the Norwegian Cancer Society, Medical Imaging Laboratory (MI-Lab, NTNU, Norway), and the Slovak Research and Development Agency under the contract LPP-0250-09.

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Authors and Affiliations

  1. MI Lab and Department of Circulation and Medical Imaging, The Norwegian University of Science and Technology, Trondheim, Norway

    Sjoerd Hak

  2. Department of Nuclear Physics and Biophysics, Faculty of Mathematics, Physics and Informatics, Comenius University, Bratislava, Slovak Republic

    Zuzana Garaiova

  3. Department of Cancer Research and Molecular Medicine, Faculty of Medicine, The Norwegian University of Science and Technology, Trondheim, Norway

    Linda Therese Olsen & Asbjørn Magne Nilsen

  4. Department of Physics, The Norwegian University of Science and Technology, Trondheim, Norway

    Catharina de Lange Davies

  5. MI Lab MR-senteret, MTFS 3. etg S, NTNU, Olav Kyrres gate 9, 7030, Trondheim, Norway

    Sjoerd Hak

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  1. Sjoerd Hak
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Correspondence to Sjoerd Hak.

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Hak, S., Garaiova, Z., Olsen, L.T. et al. The Effects of oil-in-Water Nanoemulsion Polyethylene Glycol Surface Density on Intracellular Stability, Pharmacokinetics, and Biodistribution in Tumor Bearing Mice. Pharm Res 32, 1475–1485 (2015). https://doi.org/10.1007/s11095-014-1553-6

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  • DOI: https://doi.org/10.1007/s11095-014-1553-6

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