IKK2 inhibition using TPCA-1-loaded PLGA microparticles attenuates laser-induced choroidal neovascularization and macrophage recruitment.
IKK2 inhibition using TPCA-1-loaded PLGA microparticles attenuates laser-induced choroidal neovascularization and macrophage recruitment.
复制标题
DOI：
10.1371/journal.pone.0121185
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Gaddipati S;Lu Q;Kasetti RB;Miller MC;Lu Q;Trent JO;Kaplan HJ;Li Q
通过基因缺失或药物抑制抑制NF-κB可显著减少激光诱导的脉络膜新生血管。为了实现一种选择性和强效的IKK2抑制剂2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide(TPCA-1)(分子量：279.29)的眼内持续和受控释放，我们开发了一种可生物降解的聚丙交酯-乙交酯共聚物给药系统，以进一步研究IKK2抑制的抗新生血管作用和体内生物安全性。采用溶剂挥发法制备了球形的TPCA-1 PLGA微球，其平均粒径为2.4 25m，载药率为80%。在研究期间，球后注射负载TPCA-1的PLGA微粒在视网膜中保持了持续的药物水平。未经治疗的对侧眼未检测到TPCA-1水平。用视网膜荧光素渗漏和异凝素染色的方法评价球后注射TPCA-1 PLGA微球的抗新生血管作用，结果显示激光损伤后第7天新生血管的形成明显减少。用抗F4/80抗体进行脉络膜/RPE平板染色，检测激光损伤后巨噬细胞的浸润程度。激光诱导的Vegfa和CCL2的表达被TPCA-1负载的PLGA处理所抑制。通过组织学和视动反射(OKR)测试，这种TPCA-1给药系统没有对治疗眼造成任何明显的细胞或功能毒性；也没有观察到全身毒性。我们的结论是，通过可生物降解的PLGA微粒球后注射小分子IKK2抑制剂TPCA-1，可以实现药物持续可控地释放到脉络膜/视网膜，并减弱激光诱导的CNV的发展，而不会造成明显的全身毒性。我们的结果提示，TPCA-1微球载体在治疗老年性黄斑变性和其他视网膜新生血管疾病患者的CNV方面具有潜在的临床应用价值。
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.
登录
查看更多内容
影响因子：
7.7
作者：
Marumo, T;Schini-Kerth, VB;Busse, R
通讯作者：
Busse, R
影响因子：
158.5
作者：
Brown, David M.;Kaiser, Peter K.;Schneider, Susan
通讯作者：
Schneider, Susan
影响因子：
4.4
作者：
Kompella, UB;Bandi, N;Ayalasomayajula, SP
通讯作者：
Ayalasomayajula, SP
DOI：
10.1124/jpet.104.074484
发表时间：
2005-01-01
影响因子：
3.5
作者：
Podolin, PL;Callahan, JF;Roshak, AK
通讯作者：
Roshak, AK
影响因子：
3.7
作者：
Lu H;Lu Q;Gaddipati S;Kasetti RB;Wang W;Pasparakis M;Kaplan HJ;Li Q
通讯作者：
Li Q