@article{625aaec40592469089d0e115ba5717e2,
title = "Targeted Delivery of Cell Softening Micelles to Schlemm's Canal Endothelial Cells for Treatment of Glaucoma",
abstract = "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.",
keywords = "controlled delivery, endothelium, glaucoma, latrunculin, nanoparticle",
author = "Trevor Stack and Michael Vincent and Amir Vahabikashi and Guorong Li and Perkumas, {Kristin M.} and Stamer, {W. Daniel} and Mark Johnson and Evan Scott",
note = "Funding Information: Peptide synthesis and characterization was performed at the Peptide Synthesis Core Facility of the Simpson Querrey Institute at Northwestern University. This facility has current support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-1542205). AFM studies were performed at SPID facility of Northwestern University's NUANCE Center, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-1542205). This work made use of the IMSERC at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-1542205), the State of Illinois, and the International Institute for Nanotechnology (IIN). Funding for in vitro studies was provided by NIH grant 1R01EY019696 while animal studies were funded by 1R0EY022359. Funding Information: Peptide synthesis and characterization was performed at the Peptide Synthesis Core Facility of the Simpson Querrey Institute at Northwestern University. This facility has current support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS‐1542205). AFM studies were performed at SPID facility of Northwestern University's NUANCE Center, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS‐1542205). This work made use of the IMSERC at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS‐1542205), the State of Illinois, and the International Institute for Nanotechnology (IIN). Funding for in vitro studies was provided by NIH grant 1R01EY019696 while animal studies were funded by 1R0EY022359. Publisher Copyright: {\textcopyright} 2020 Wiley-VCH GmbH",
year = "2020",
month = oct,
day = "1",
doi = "10.1002/smll.202004205",
language = "English (US)",
volume = "16",
journal = "Small",
issn = "1613-6810",
publisher = "Wiley-VCH Verlag",
number = "43",
}