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Published on: January 2, 2017
Evading immune cell uptake and clearance requires PEG grafting at densities substantially exceeding the minimum for
Qi Yang1, Stephen W Jones, Christina L Parker
1Division of Molecular Pharmaceutics, ‡Department of Cell Biology and Physiology, §Division of Pharmacotherapy and Experimental Therapeutics, ∥Department of Pharmacology, ⊥UNC Lineberger Cancer Center, ¶Carolina Center of Cancer Nanotechnology Excellence, #Howard Hughes Medical Institute, and ▽UNC/NCSU Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
Abstract:
Coating nanoparticles with polyethylene glycol (PEG), which reduces particle uptake and clearance by immune cells, is routinely used to extend the circulation times of nanoparticle therapeutics. Nevertheless, due to technical hurdles in quantifying the extent of PEG grafting, as well as in generating very dense PEG coatings, few studies have rigorously explored the precise PEG grafting density necessary to achieve desirable "stealth" properties. Here, using polymeric nanoparticles with precisely tunable PEG grafting, we found that, for a wide range of PEG lengths (0.6-20 kDa), PEG coatings at densities substantially exceeding those required for PEG to adopt a "brush" conformation are exceptionally resistant to uptake by cultured human macrophages, as well as primary peripheral blood leukocytes. Less than 20% of these nanoparticles were cleared from the blood after 2 h (t1/2 ∼ 14 h) in BALB/c mice, whereas slightly less densely PEGylated and uncoated control particles were both virtually eliminated within 2 h. Our results suggest that the stealth properties of PEG-coated nanoparticles are critically dependent on achieving PEG grafting at densities exceeding those required for brush conformation.
