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High-Density Branched PEGylation for Nanoparticle Drug Delivery

  • 2022 CMBE Young Innovators
  • Published:
Cellular and Molecular Bioengineering Aims and scope Submit manuscript

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.

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Acknowledgments

We thank Dr. Steven Jay and Dr. Margaret Scull at the University of Maryland for generously providing HEK-293T and A549 cells, respectively. We thank Dr. Natalie West, Dr. Jung Soo Suk, and Dr. Justin Hanes at Johns Hopkins University School of Medicine for providing the CF sputum used in our work through their IRB-approved study. We acknowledge the BioWorkshop core facility in the Fischell Department of Bioengineering at the University of Maryland for use of their dynamic light scattering instrument and microplate reader.

Funding

This work was supported by the American Lung Association Innovation Award, Burroughs Wellcome Fund Career Award at the Scientific Interface, NSF CAREER Award 2047794, and UMD-NCI Partnership for Integrative Cancer Research.

Conflict of interest

Devorah Cahn and Gregg Duncan declare no conflicts of interest.

Human Subjects Research Ethics Statement

Human mucus was collected under an IRB-approved protocol at the Johns Hopkins University of School of Medicine (Study NA_00046768). Spontaneously expectorated sputum samples were collected after receiving written informed consent from all patients included in the study. All patient samples were de-identified and referred to by numerical ID only.

Animal Research Ethics Statement

No animal studies were performed in this research.

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Authors and Affiliations

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

    Devorah Cahn & Gregg A. Duncan

  2. Biophysics Program, University of Maryland, College Park, MD, 20742, USA

    Gregg A. Duncan

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  1. Devorah Cahn
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Correspondence to Gregg A. Duncan.

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Associate Editor Michael R. King oversaw the review of this article.

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Cahn, D., Duncan, G.A. High-Density Branched PEGylation for Nanoparticle Drug Delivery. Cel. Mol. Bioeng. 15, 355–366 (2022). https://doi.org/10.1007/s12195-022-00727-x

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