机构：[1]Departments of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States of America[2]James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, United States of America[3]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,研究所眼科研究所首都医科大学附属北京同仁医院首都医科大学附属同仁医院[5]Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky, United States of America
The inhibition of NF-kappa B 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 1/4m 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 retro-bulbarly 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.
基金：
National Eye InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Eye Institute (NEI) [R01-EY019891, EY021548]; National Institute of General Medical SciencesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [1P30GM106396]; Research to Prevent Blindness Ernest & Elizabeth Althouse Special Scholar Award; NATIONAL EYE INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Eye Institute (NEI) [R01EY019891] Funding Source: NIH RePORTER; NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCESUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [P30GM106396] Funding Source: NIH RePORTER
第一作者机构：[1]Departments of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States of America[2]James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, United States of America
通讯作者：
通讯机构：[1]Departments of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, United States of America[2]James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky, United States of America
推荐引用方式(GB/T 7714)：
Gaddipati Subhash,Lu Qingxian,Kasetti Ramesh Babu,et al.IKK2 Inhibition Using TPCA-1-Loaded PLGA Microparticles Attenuates Laser-Induced Choroidal Neovascularization and Macrophage Recruitment[J].PLOS ONE.2015,10(3):doi:10.1371/journal.pone.0121185.
APA：
Gaddipati, Subhash,Lu, Qingxian,Kasetti, Ramesh Babu,Miller, M. Clarke,Lu, Qingjun...&Li, Qiutang.(2015).IKK2 Inhibition Using TPCA-1-Loaded PLGA Microparticles Attenuates Laser-Induced Choroidal Neovascularization and Macrophage Recruitment.PLOS ONE,10,(3)
MLA：
Gaddipati, Subhash,et al."IKK2 Inhibition Using TPCA-1-Loaded PLGA Microparticles Attenuates Laser-Induced Choroidal Neovascularization and Macrophage Recruitment".PLOS ONE 10..3(2015)
