Ligon Research Center of Vision, Wayne State University, Detroit, MI, USA.
Biomaterials. 2012 Jan;33(3):979-88. doi: 10.1016/j.biomaterials.2011.10.010. Epub 2011 Nov 1.
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 μg of FA conjugated to 7 μg 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.
视网膜神经炎症由激活的小胶质细胞介导，在年龄相关性黄斑变性和视网膜色素变性中感光细胞和视网膜色素上皮细胞的丧失发病机制中起关键作用。使用端羟基聚酰胺胺（PAMAM）树枝状大分子-药物偶联纳米器件探索了靶向药物疗法以减轻视网膜神经炎症。我们表明，在玻璃体内给药后，PAMAM 树枝状大分子在两种视网膜变性大鼠模型中选择性地定位于激活的外视网膜小胶质细胞内，但不在健康对照的视网膜中。这种依赖于病理学的生物分布被用于药物递送，通过将氟轻松醋酸酯共价偶联到树枝状大分子上。该偶联物在 90 天内以持续的方式释放药物。在为期四周的 RCS 大鼠视网膜变性模型中评估了体内功效，此时发生视网膜变性的高峰期。玻璃体腔注射 1μg 与 7μg 树枝状大分子偶联的 FA 能够阻止视网膜变性，保留感光细胞外核细胞计数，并减轻激活的小胶质细胞，持续整整一个月。这些研究表明，PAMAM 树枝状大分子（无靶向配体）具有内在的能力，可选择性地定位于激活的小胶质细胞，并可将药物递送到这些细胞内以进行持续治疗视网膜神经炎症。
