Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration
Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration
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DOI：
10.1016/j.biomaterials.2011.10.010
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发表时间：
2012-01-01
期刊：
影响因子：
14
通讯作者：
Kannan, Rangaramanujam M.
中科院分区：
文献类型：
--
作者：
Iezzi, Raymond;Guru, Bharath R.;Kannan, Rangaramanujam M.
活化的小胶质细胞介导的视网膜神经炎症在老年性黄斑变性和视网膜色素变性的光感受器和视网膜色素上皮细胞丢失的发病机制中起关键作用。利用端羟基聚酰胺胺(PAMAM)树枝状大分子-药物结合纳米器件，探索了减轻视网膜神经炎症的靶向药物疗法。我们发现，在玻璃体内给药时，PAMAM树状大分子选择性地定位于两种视网膜变性模型大鼠激活的视网膜外小胶质细胞内，而不是健康对照组的视网膜。这种依赖于病理的生物分布被用来给药，通过共价连接氟喹诺酮丙酮到树枝状大分子。该结合物以持续的方式释放药物超过90天。使用皇家外科医师学会(RCS)的大鼠视网膜变性模型，在四周的视网膜变性高峰期内评估了体内疗效。一次玻璃体内注射1mgFA和7mg树枝状大分子能够阻止视网膜变性，保存光感受器外核细胞计数，并减弱激活的小胶质细胞，整整一个月。这些研究表明，PAMAM树状大分子(没有靶向配体)具有选择性地定位于激活的小胶质细胞的内在能力，并可以在这些细胞内持续输送药物用于治疗视网膜神经炎。(C)2011爱思唯尔有限公司。保留所有权利。
Retinal neuroinflammation, mediated by activated microglia, plays a key role in the pathogenesis of photoreceptor and retinal pigment epithelial cell loss in age-related macular degeneration and retinitis pigmentosa. Targeted drug therapy for attenuation of neuroinflammation in the retina was explored using hydroxyl-terminated polyamidoamine (PAMAM) dendrimer-drug conjugate nanodevices. We show that, upon intravitreal administration, PAMAM dendrimers selectively localize within activated outer retinal microglia in two rat models of retinal degeneration, but not in the retina of healthy controls. This pathology-dependent biodistribution was exploited for drug delivery, by covalently conjugating fluocinolone acetonide to the dendrimer. The conjugate released the drug in a sustained manner over 90 days. In vivo efficacy was assessed using the Royal College of Surgeons (RCS) rat retinal degeneration model over a four-week period when peak retinal degeneration occurs. One intravitreal injection of 1 mu g of FA conjugated to 7 mu g of the dendrimer was able to arrest retinal degeneration, preserve photoreceptor outer nuclear cell counts, and attenuate activated microglia, for an entire month. These studies suggest that PAMAM dendrimers (with no targeting ligands) have an intrinsic ability to selectively localize in activated microglia, and can deliver drugs inside these cells for a sustained period for the treatment of retinal neuroinflammation. (C) 2011 Elsevier Ltd. All rights reserved.