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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • 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