Format

Send to

Choose Destination

See 1 citation found by title matching your search:

PLoS One. 2015 Mar 24;10(3):e0121185. doi: 10.1371/journal.pone.0121185. eCollection 2015.

IKK2 inhibition using TPCA-1-loaded PLGA microparticles attenuates laser-induced choroidal neovascularization and macrophage recruitment.

Author information

1
Departments of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States of America; James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, United States of America.
2
Departments of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States of America.
3
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, United States of America; Department of Chemistry and Biochemistry, University of North Georgia, Oakwood, Georgia, United States of America.
4
Beijing Institute of Ophthalmology, Beijing Tong-Ren Eye Center, Capital Medical University, Beijing, China.
5
James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, United States of America; Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky, United States of America.

Abstract

The inhibition of NF-κB by genetic deletion or pharmacological inhibition of IKK2 significantly reduces laser-induced choroid neovascularization (CNV). To achieve a sustained and controlled intraocular release of a selective and potent IKK2 inhibitor, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1) (MW: 279.29), we developed a biodegradable poly-lactide-co-glycolide (PLGA) polymer-delivery system to further investigate the anti-neovascularization effects of IKK2 inhibition and in vivo biosafety using laser-induced CNV mouse model. The solvent-evaporation method produced spherical TPCA-1-loaded PLGA microparticles characterized with a mean diameter of 2.4 ¼m and loading efficiency of 80%. Retrobulbar administration of the TPCA-1-loaded PLGA microparticles maintained a sustained drug level in the retina during the study period. No detectable TPCA-1 level was observed in the untreated contralateral eye. The anti-CNV effect of retrobulbarly administrated TPCA-1-loaded PLGA microparticles was assessed by retinal fluorescein leakage and isolectin staining methods, showing significantly reduced CNV development on day 7 after laser injury. Macrophage infiltration into the laser lesion was attenuated as assayed by choroid/RPE flat-mount staining with anti-F4/80 antibody. Consistently, laser induced expressions of Vegfa and Ccl2 were inhibited by the TPCA-1-loaded PLGA treatment. This TPCA-1 delivery system did not cause any noticeable cellular or functional toxicity to the treated eyes as evaluated by histology and optokinetic reflex (OKR) tests; and no systemic toxicity was observed. We conclude that retrobulbar injection of the small-molecule IKK2 inhibitor TPCA-1, delivered by biodegradable PLGA microparticles, can achieve a sustained and controllable drug release into choroid/retina and attenuate laser-induced CNV development without causing apparent systemic toxicity. Our results suggest a potential clinical application of TPCA-1 delivered by microparticles in treatment of CNV in the patients with age-related macular degeneration and other retinal neovascularization diseases.

PMID:
25803615
PMCID:
PMC4372421
DOI:
10.1371/journal.pone.0121185
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center