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

Publication ,  Journal Article
Vincent, MP; Stack, T; Vahabikashi, A; Li, G; Perkumas, KM; Ren, R; Gong, H; Stamer, WD; Johnson, M; Scott, EA
Published in: ACS applied materials & interfaces
July 2021

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 (SC) 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 SC endothelial cells and can be exploited for targeted drug delivery. Here, we validate FLT4 receptors as clinically relevant targets on SC 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 SC cells while simultaneously decreasing the uptake by off-target vascular endothelial cells. Using a paired longitudinal IOP study in vivo, we show that this enhanced targeting of SC cells translates to IOP reductions that are sustained for a significantly longer time as compared to controls. Confocal microscopy of murine anterior segment tissue confirmed nanocarrier localization to SC within 1 h after intracameral administration. This work demonstrates that steric effects between surface-displayed ligands and PEG coronas significantly impact the 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.

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Published In

ACS applied materials & interfaces

DOI

EISSN

1944-8252

ISSN

1944-8244

Publication Date

July 2021

Volume

13

Issue

28

Start / End Page

32823 / 32836

Related Subject Headings

  • Vascular Endothelial Growth Factor Receptor-3
  • Thiazolidines
  • Sulfides
  • Polyethylene Glycols
  • Peptides
  • Nanoscience & Nanotechnology
  • Molecular Structure
  • Micelles
  • Mice, Inbred C57BL
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
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Vincent, M. P., Stack, T., Vahabikashi, A., Li, G., Perkumas, K. M., Ren, R., … Scott, E. A. (2021). Surface Engineering of FLT4-Targeted Nanocarriers Enhances Cell-Softening Glaucoma Therapy. ACS Applied Materials & Interfaces, 13(28), 32823–32836. https://doi.org/10.1021/acsami.1c09294
Vincent, Michael P., Trevor Stack, Amir Vahabikashi, Guorong Li, Kristin M. Perkumas, Ruiyi Ren, Haiyan Gong, W Daniel Stamer, Mark Johnson, and Evan A. Scott. “Surface Engineering of FLT4-Targeted Nanocarriers Enhances Cell-Softening Glaucoma Therapy.ACS Applied Materials & Interfaces 13, no. 28 (July 2021): 32823–36. https://doi.org/10.1021/acsami.1c09294.
Vincent MP, Stack T, Vahabikashi A, Li G, Perkumas KM, Ren R, et al. Surface Engineering of FLT4-Targeted Nanocarriers Enhances Cell-Softening Glaucoma Therapy. ACS applied materials & interfaces. 2021 Jul;13(28):32823–36.
Vincent, Michael P., et al. “Surface Engineering of FLT4-Targeted Nanocarriers Enhances Cell-Softening Glaucoma Therapy.ACS Applied Materials & Interfaces, vol. 13, no. 28, July 2021, pp. 32823–36. Epmc, doi:10.1021/acsami.1c09294.
Vincent MP, Stack T, Vahabikashi A, Li G, Perkumas KM, Ren R, Gong H, Stamer WD, Johnson M, Scott EA. Surface Engineering of FLT4-Targeted Nanocarriers Enhances Cell-Softening Glaucoma Therapy. ACS applied materials & interfaces. 2021 Jul;13(28):32823–32836.
Journal cover image

Published In

ACS applied materials & interfaces

DOI

EISSN

1944-8252

ISSN

1944-8244

Publication Date

July 2021

Volume

13

Issue

28

Start / End Page

32823 / 32836

Related Subject Headings

  • Vascular Endothelial Growth Factor Receptor-3
  • Thiazolidines
  • Sulfides
  • Polyethylene Glycols
  • Peptides
  • Nanoscience & Nanotechnology
  • Molecular Structure
  • Micelles
  • Mice, Inbred C57BL
  • Mice