Size- and charge-dependent non-specific uptake of PEGylated nanoparticles by macrophages

Shann S Yu^1,2, Cheryl M Lau¹, Susan N Thomas³, W Gray Jerome⁴, David J Maron⁵, James H Dickerson^2,6, Jeffrey A Hubbell³, Todd D Giorgio<sup>1,2,7,8

1</sup>Department of Biomedical Engineering, Vanderbilt University, Nashville, ²Vanderbilt Institute of Nanoscale Science and Engineering, Nashville, TN, USA; ³Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland, ⁴Department of Pathology, Vanderbilt University Medical Center, Nashville, ⁵Vanderbilt Heart and Vascular Institute, Nashville, ⁶Department of Physics and Astronomy, Vanderbilt University, Nashville, ⁷Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, ⁸Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA

Abstract: The assessment of macrophage response to nanoparticles is a central component in the evaluation of new nanoparticle designs for future in vivo application. This work investigates which feature, nanoparticle size or charge, is more predictive of non-specific uptake of nanoparticles by macrophages. This was investigated by synthesizing a library of polymer-coated iron oxide micelles, spanning a range of 30–100 nm in diameter and -23 mV to +9 mV, and measuring internalization into macrophages in vitro. Nanoparticle size and charge both contributed towards non-specific uptake, but within the ranges investigated, size appears to be a more dominant predictor of uptake. Based on these results, a protease-responsive nanoparticle was synthesized, displaying a matrix metalloproteinase-9 (MMP-9)-cleavable polymeric corona. These nanoparticles are able to respond to MMP-9 activity through the shedding of 10–20 nm of hydrodynamic diameter. This MMP-9-triggered decrease in nanoparticle size also led to up to a six-fold decrease in nanoparticle internalization by macrophages and is observable by T₂-weighted magnetic resonance imaging. These findings guide the design of imaging or therapeutic nanoparticles for in vivo targeting of macrophage activity in pathologic states.

Keywords: macrophage targeting, poly(ethylene glycol) (PEG), poly(propylene sulfide) (PPS), iron oxides, opsonization

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