Subconjunctivally administered celecoxib-PLGA microparticles sustain retinal drug levels and alleviate diabetes-induced oxidative stress in a rat model
Subconjunctivally administered celecoxib-PLGA microparticles sustain retinal drug levels and alleviate diabetes-induced oxidative stress in a rat model
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DOI：
10.1016/j.ejphar.2005.02.019
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发表时间：
2005-03-28
影响因子：
5
通讯作者：
Kompella, UB
中科院分区：
文献类型：
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作者：
Ayalasomayajula, SP;Kompella, UB
我们之前已经报道，反复口服塞来昔布，一种选择性环氧合酶-2(COX-2)抑制剂，减少糖尿病诱导的视网膜血管内皮生长因子(VEGF)的表达[Ayalasomayajula，S.P.，Kompella，U.B.，2003。塞来昔布是一种选择性环氧合酶-2抑制剂，可抑制链脲佐菌素诱导的糖尿病大鼠模型视网膜血管内皮生长因子的表达和血管渗漏。EUJ Pharmacol 458,283-289]，而且在结膜下给药后，视网膜塞来昔布的释放可提高数倍[Ayalasomayajula，S.P.，Kompella，U.B.，2004]。与全身给药相比，结膜下给药后塞来昔布的视网膜释放量高出数倍。药典第21条，1797-1804条]。本研究的目的是在链脲佐菌素诱导的糖尿病大鼠模型中，确定塞来昔布聚合物微粒在结膜下给药后是否维持视网膜药物浓度，并减轻糖尿病引起的氧化应激。采用溶剂挥发法制备了可生物降解的聚丙交酯-乙交酯(PLGA；85：15)塞来昔布微球，并对其尺寸、形态、包封率和体外释放性能进行了表征。将塞来昔布-PLGA微粒或含75 mU g塞来昔布的PLGA微球或溶液注入SD大鼠一侧(同侧)结膜下，分别于第1、7、14天用高效液相色谱法测定同侧和对侧眼视网膜、玻璃体、晶状体和角膜的药物浓度。采用荧光分光光度法和比色法测定视网膜还原型谷胱甘肽(GSH)、氧化还原型谷胱甘肽(GSSG)、硫代巴比妥酸反应物质和4-羟基壬烯醛含量，观察塞来昔布-PLGA微球结膜下注射对糖尿病大鼠视网膜氧化应激的影响。溶剂挥发法制备的塞来昔布-PLGA微球平均粒径为3.9±0.6微米，载药率为68.5%。在为期49天的体外释放研究中，这些微粒持续了塞来昔布的释放。在为期14天的研究中，结膜下注射塞来昔布-PLGA微粒维持了大鼠视网膜和其他眼组织的药物水平。对侧眼未检测到塞来昔布浓度。塞来昔布-聚乳酸微球显著抑制糖尿病引起的硫代巴比妥酸反应物质(P=0.012)和4-羟基壬烯醛(P=0.029)水平的升高。对糖尿病所致的GSH耗竭和GSSH/GSH比值升高也有抑制作用，但无统计学意义(P=0.12)。因此，在结膜下给药后，塞来昔布-PLGA微粒维持了视网膜塞来昔布的释放，并抑制了糖尿病引起的视网膜氧化损伤，表明它们在治疗糖尿病引起的视网膜异常方面具有潜在的用途。(C)2005 Elsevier B.V.保留所有权利。
We have previously reported that repeated oral doses of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, reduced diabetes-induced retinal vascular endothelial growth factor (VEGF) expression [Ayalasomayajula, S.P., Kompella, U.B., 2003. Celecoxib, a selective cyclooxygenase-2 inhibitor, inhibits retinal vascular endothelial growth factor expression and vascular leakage in a streptozotocin-induced diabetic rat model. Eur J Pharmacol 458, 283-289] and that retinal celecoxib delivery can be improved by several-fold following subconjunctival administration [Ayalasomayajula, S.P., Kompella, U.B., 2004. Retinal delivery of celecoxib is several-fold higher following subconjunctival administration compared to systemic administration. Pharm Res 21, 1797-1804]. The objective of the current study was to determine whether polymeric microparticles of celecoxib sustain retinal drug levels following subconjunctival administration and alleviate diabetes-induced oxidative stress in a streptozotocin-induced diabetic rat model. Biodegradable poly (lactide-co-glycolide) (PLGA; 85:15) microparticles of celecoxib were prepared using solvent evaporation method and characterized for their size, morphology, encapsulation efficiencies, and in vitro release. The celecoxib-PLGA microparticles or solution containing 75 mu g of celecoxib was administered subconjunctivally to one eye (ipsilateral) of Sprague Dawley rats and drug levels in the retina, vitreous, lens, and cornea of ipsilateral and contralateral eyes were determined on 1, 7, and 14 days using high-performance liquid chromatography (HPLC). The effect of subconjunctivally administered celecoxib-PLGA microparticles on oxidative stress in day 14 diabetic rat retinas was determined by measuring the retinal glutathione (reduced (GSH) and oxidized (GSSG)), thiobarbituric acid reactive substances, and 4-hydroxynonenal levels using spectrofluorometric and colorimetric methods. Solvent evaporation method produced spherical celecoxib-PLGA microparticles with mean diameters of 3.9 +/- 0.6 mu m and 68.5% loading, efficiency. These microparticles sustained celecoxib release during the 49-day in vitro release study. Subconjunctivally administered celecoxib-PLGA microparticles sustained retinal and other ocular tissue drug levels during the 14-day study in rats. No detectable celecoxib levels were observed in the contralateral eye. The celecoxib-PLGA microparticles significantly inhibited the diabetes-induced increases in thiobarbituric acid reactive substances (P=0.012) and 4-hydroxynonenal levels (P=0.029). The particles also inhibited the GSH depletion and the increase in GSSH/GSH ratio associated with diabetes but the effects were not statistically significant (P=0.12). Thus, following subconjunctival administration, celecoxib-PLGA microparticles sustained retinal celecoxib delivery and inhibited diabetes-induced retinal oxidative damage, indicating their potential usefulness in treating diabetes-induced retinal abnormalities. (c) 2005 Elsevier B.V. All rights reserved.