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Surface Engineering of FLT4-Targeted Nanocarriers Enhances Cell-Softening Glaucoma Therapy

Michael P. Vincent, Trevor Stack, Amir Vahabikashi, Guorong Li, Kristin M. Perkumas, Ruiyi Ren, Haiyan Gong, W. Daniel Stamer, Mark Johnson, Evan A. Scott
doi: https://doi.org/10.1101/2021.05.19.444878
Michael P. Vincent
1Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
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Trevor Stack
1Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
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Amir Vahabikashi
2Department of Cell and Developmental Biology, Northwestern University, Northwestern University, Chicago, IL 60611, USA
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Guorong Li
3Department of Ophthalmology, Duke University, Durham, NC 27710, USA
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Kristin M. Perkumas
3Department of Ophthalmology, Duke University, Durham, NC 27710, USA
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Ruiyi Ren
4Department of Ophthalmology, Boston University School of Medicine, Boston, MA 02118, USA
5Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA
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Haiyan Gong
4Department of Ophthalmology, Boston University School of Medicine, Boston, MA 02118, USA
5Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA
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W. Daniel Stamer
3Department of Ophthalmology, Duke University, Durham, NC 27710, USA
6Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA
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Mark Johnson
1Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
7Department of Ophthalmology, Northwestern University, Chicago, IL 60611, USA
8Department of Mechanical Engineering, Northwestern University, Evanston, IL 60208, USA
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Evan A. Scott
1Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
9Simpson Querrey Institute, Northwestern University, Chicago, IL 60611, USA
10Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA
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  • For correspondence: evan.scott@northwestern.edu
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ABSTRACT

Primary open-angle glaucoma is associated with elevated intraocular pressure (IOP) that damages the optic nerve and leads to gradual vision loss. Several agents that reduce the stiffness of pressure-regulating Schlemm’s canal endothelial cells, in the conventional outflow pathway of the eye, lower IOP in glaucoma patients and are approved for clinical use. However, poor drug penetration and uncontrolled biodistribution limit their efficacy and produce local adverse effects. Compared to other ocular endothelia, FLT4/VEGFR3 is expressed at elevated levels by Schlemm’s canal endothelial cells and can be exploited for targeted drug delivery. Here, we validate FLT4 receptors as a clinically relevant target on Schlemm’s canal cells from glaucomatous human donors and engineer polymeric self-assembled nanocarriers displaying lipid-anchored targeting ligands that optimally engage this receptor. Targeting constructs were synthesized as lipid-PEGX-peptide, differing in the number of PEG spacer units (x), and were embedded in micelles. We present a novel proteolysis assay for quantifying ligand accessibility that we employ to design and optimize our FLT4-targeting strategy for glaucoma nanotherapy. Peptide accessibility to proteases correlated with receptor-mediated targeting enhancements. Increasing the accessibility of FLT4-binding peptides enhanced nanocarrier uptake by Schlemm’s canal cells while simultaneously decreasing uptake by off-target vascular endothelial cells. Using a paired longitudinal IOP study in vivo, we show this enhanced targeting of Schlemm’s canal cells translates to IOP reductions that are sustained for a significantly longer time as compared to controls. Histological analysis of murine anterior segment tissue confirmed nanocarrier localization to Schlemm’s canal within one hour after intracameral administration. This work demonstrates that steric effects between surface-displayed ligands and PEG coronas significantly impact targeting performance of synthetic nanocarriers across multiple biological scales. Minimizing the obstruction of modular targeting ligands by PEG measurably improved the efficacy of glaucoma nanotherapy and is an important consideration for engineering PEGylated nanocarriers for targeted drug delivery.

Competing Interest Statement

The authors have declared no competing interest.

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Posted May 20, 2021.
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Surface Engineering of FLT4-Targeted Nanocarriers Enhances Cell-Softening Glaucoma Therapy
Michael P. Vincent, Trevor Stack, Amir Vahabikashi, Guorong Li, Kristin M. Perkumas, Ruiyi Ren, Haiyan Gong, W. Daniel Stamer, Mark Johnson, Evan A. Scott
bioRxiv 2021.05.19.444878; doi: https://doi.org/10.1101/2021.05.19.444878
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Surface Engineering of FLT4-Targeted Nanocarriers Enhances Cell-Softening Glaucoma Therapy
Michael P. Vincent, Trevor Stack, Amir Vahabikashi, Guorong Li, Kristin M. Perkumas, Ruiyi Ren, Haiyan Gong, W. Daniel Stamer, Mark Johnson, Evan A. Scott
bioRxiv 2021.05.19.444878; doi: https://doi.org/10.1101/2021.05.19.444878

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