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

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.

• Authors: Subhash Gaddipati, Qingxian Lu, Ramesh Babu Kasetti, M Clarke Miller, Qingjun Lu, John O Trent, Henry J Kaplan, Qiutang Li
• Journal: PloS one (PLoS One) Vol. 10 Issue 3 Pg. e0121185 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25803615 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Drug Carriers
• Protein Kinase Inhibitors
• Thiophenes
• Polylactic Acid-Polyglycolic Acid Copolymer
• Polyglycolic Acid
• Lactic Acid
• 2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide
• I-kappa B Kinase
• Ikbkb protein, mouse

Topics

• Amides (administration & dosage, chemistry)
• Animals
• Choroidal Neovascularization (drug therapy, pathology)
• Disease Models, Animal
• Drug Carriers (administration & dosage, chemistry)
• Female
• I-kappa B Kinase (antagonists & inhibitors)
• Lactic Acid (administration & dosage, chemistry)
• Macrophages (cytology, drug effects, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Polyglycolic Acid (administration & dosage, chemistry)
• Polylactic Acid-Polyglycolic Acid Copolymer
• Protein Kinase Inhibitors (administration & dosage, chemistry)
• Thiophenes (administration & dosage, chemistry)