High-Density Branched PEGylation for Nanoparticle Drug Delivery

Devorah Cahn; Gregg A Duncan

doi:10.1007/s12195-022-00727-x

High-Density Branched PEGylation for Nanoparticle Drug Delivery

Cell Mol Bioeng. 2022 Jul 5;15(5):355-366. doi: 10.1007/s12195-022-00727-x. eCollection 2022 Oct.

Authors

Devorah Cahn¹, Gregg A Duncan^{1

2}

Affiliations

¹ Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742 USA.
² Biophysics Program, University of Maryland, College Park, MD 20742 USA.

Abstract

Introduction: The surface modification of nanoparticles (NP) with a dense layer of polyethylene glycol (PEG) has been widely used to improve NP circulation time, bioavailability, and diffusion through biological barriers [e.g. extracellular matrix (ECM), mucus]. While linear PEG coatings are commonly used, branched PEG coatings have not been widely explored as a design parameter for NP drug delivery systems.

Methods: NPs were densely coated with either linear 2, 5, 10 kDa linear PEG or with 10 kDa star-shaped, 4-arm branched PEG. NP cellular uptake was evaluated in HEK-293T and A549 cells. NP stability was evaluated in fetal bovine serum over 24 h using dynamic light scattering. Diffusion of NPs within a Matrigel ECM model and sputum (mucus) collected from individuals with cystic fibrosis (CF) lung disease were analyzed through multiple particle tracking.

Results: PEG-coated NPs appeared more stable in serum compared to uncoated NPs, but the reduction in total protein adsorbed was most significant for branched PEG coated NP. All PEGylated NPs had similar cellular uptake in HEK-293T and A549 cells. Interestingly, branched-PEG coated NPs had the largest diffusion coefficient and moved most rapidly through Matrigel. However in CF mucus, linear 2 and 5 kDa PEG coated NPs had the largest fraction of rapidly diffusing particles while branched PEG coated NPs had less hindered mobility compared to linear 10 kDa PEG coated NPs.

Conclusion: Branched PEGylation may have the potential to increase NP efficiency in reaching target cells based on an apparent increase in diffusion through an ECM model while maintaining NP stability and uptake in target cells comparable to their linear PEG counterparts.

Keywords: Extracellular matrix; Nanomedicine; PEGylation.