Targeted Delivery of Cell Softening Micelles to Schlemm's Canal Endothelial Cells for Treatment of Glaucoma.

Journal Article (Journal Article)

Increased stiffness of the Schlemm's canal (SC) endothelium in the aqueous humor outflow pathways has been associated with elevated intraocular pressure (IOP) in glaucoma. Novel treatments that relax this endothelium, such as actin depolymerizers and rho kinase inhibitors, are in development. Unfortunately, these treatments have undesirable off-target effects and a lower than desired potency. To address these issues, a targeted PEG-b-PPS micelle loaded with actin depolymerizer latrunculin A (tLatA-MC) is developed. Targeting of SC cells is achieved by modifying the micelle surface with a high affinity peptide that binds the VEGFR3/FLT4 receptor, a lymphatic lineage marker found to be highly expressed by SC cells relative to other ocular cells. During in vitro optimization, increasing the peptide surface density increased micellar uptake in SC cells while unexpectedly decreasing uptake by human umbilical vein endothelial cells (HUVEC). The functional efficacy of tLatA-MC, as measured by decreased SC cell stiffness compared to non-targeted micelles (ntLatA-MC) or targeted blank micelles (tBL-MC), is verified using atomic force microscopy. tLatA-MC reduced IOP in an in vivo mouse model by 30-50%. The results validate the use of a cell-softening nanotherapy to selectively modulate stiffness of SC cells for therapeutic reduction of IOP and treatment of glaucoma.

Full Text

Duke Authors

Cited Authors

  • Stack, T; Vincent, M; Vahabikashi, A; Li, G; Perkumas, KM; Stamer, WD; Johnson, M; Scott, E

Published Date

  • October 2020

Published In

Volume / Issue

  • 16 / 43

Start / End Page

  • e2004205 -

PubMed ID

  • 33015961

Pubmed Central ID

  • PMC7647937

Electronic International Standard Serial Number (EISSN)

  • 1613-6829

Digital Object Identifier (DOI)

  • 10.1002/smll.202004205

Language

  • eng

Conference Location

  • Germany