State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, PR China; Department of Ophthalmology, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore, MD 21231, USA; Center for Nanomedicine, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore, MD 21231, USA.
Department of Ophthalmology, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore, MD 21231, USA; Center for Nanomedicine, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore, MD 21231, USA; Department of Ophthalmology, Myopia Key Laboratory of Health, Eye & ENT Hospital of Fudan University, Shanghai 200031, PR China.
J Control Release. 2019 Feb 28;296:68-80. doi: 10.1016/j.jconrel.2019.01.018. Epub 2019 Jan 17.
Noninfectious uveitis is a potentially blinding ocular condition that often requires treatment with corticosteroids to prevent inflammation-related ocular complications. Severe forms of uveitis such as panuveitis that affects the whole eye often require a combination of topical and either regional or systemic corticosteroid. Regional corticosteroids are currently delivered inside the eye by intravitreal injection (e.g. Ozurdex®, an intravitreal dexamethasone implant). Intravitreal injection is associated with rare but potentially serious side effects, including endophthalmitis, retinal and vitreous hemorrhage, and retinal detachment. Subconjunctival (SCT) injection is a less invasive option that is a common route used for post-surgical drug administration and treatment of infection and severe inflammation. However, it is the water soluble form of dexamethasone, dexamethasone sodium phosphate (DSP), that has been demonstrated to achieve high intraocular penetration with subconjunctival injection. It is difficult to load highly water soluble drugs, such as DSP, and achieve sustained drug release using conventional encapsulation methods. We found that use of carboxyl-terminated poly(lactic-co-glycolic acid) (PLGA) allowed encapsulation of DSP into biodegradable nanoparticles (NP) with relatively high drug content (6% w/w) if divalent zinc ions were used as an ionic "bridge" between the PLGA and DSP. DSP-Zn-NP had an average diameter of 210 nm, narrow particle size distribution (polydispersity index ~0.1), and near neutral surface charge (-9 mV). DSP-Zn-NP administered by SCT injection provided detectable DSP levels in both the anterior chamber and vitreous chamber of the eye for at least 3 weeks. In a rat model of experimental autoimmune uveitis (EAU), inflammation was significantly reduced in both the front and back of the eye in animals that received a single SCT injection of DSP-Zn-NP as compared to animals that received either aqueous DSP solution or phosphate buffered saline (PBS). DSP-Zn-NP efficacy was evidenced by a reduced clinical disease score, decreased expression of various inflammatory cytokines, and preserved retinal structure and function. Furthermore, SCT DSP-Zn-NP significantly reduced microglia cell density in the retina, a hallmark of EAU in rats. DSP-Zn-NP hold promise as a new strategy to treat noninfectious uveitis and potentially other ocular inflammatory disorders.
非感染性葡萄膜炎是一种潜在致盲性眼病，常需用皮质类固醇治疗以预防炎症相关的眼部并发症。全葡萄膜炎等严重形式的葡萄膜炎通常需要联合局部和（或）全身皮质类固醇治疗。目前，眼部区域皮质类固醇通过玻璃体内注射（例如，Ozurdex®，一种玻璃体内地塞米松植入物）递送至眼内。玻璃体内注射与罕见但潜在严重的副作用相关，包括眼内炎、视网膜和玻璃体积血以及视网膜脱离。结膜下（SCT）注射是一种侵袭性较小的选择，是用于术后药物给药和治疗感染和严重炎症的常见途径。然而，已证实结膜下注射水溶性形式的地塞米松磷酸二钠（DSP）可实现高眼内穿透率。使用常规包封方法很难负载高度水溶性药物（如 DSP）并实现持续药物释放。我们发现，如果使用二价锌离子作为 PLGA 和 DSP 之间的离子“桥”，则可以使用羧基封端的聚（乳酸-共-羟基乙酸）（PLGA）将 DSP 包封成具有相对高药物含量（6%w/w）的可生物降解纳米颗粒（NP）。DSP-Zn-NP 的平均直径为 210nm，粒径分布较窄（多分散指数约为 0.1），表面带负电荷（-9mV）。通过 SCT 注射给予 DSP-Zn-NP 后，在眼的前房和玻璃体内至少可检测到 3 周的 DSP 水平。在实验性自身免疫性葡萄膜炎（EAU）大鼠模型中，与接受 DSP 水溶液或磷酸盐缓冲盐水（PBS）单一 SCT 注射的动物相比，接受 DSP-Zn-NP 单一 SCT 注射的动物眼前后部的炎症均显著减轻。DSP-Zn-NP 的疗效表现为临床疾病评分降低、各种炎症细胞因子的表达减少以及视网膜结构和功能保持。此外，SCT DSP-Zn-NP 可显著降低大鼠 EAU 中视网膜内小胶质细胞密度。DSP-Zn-NP 有望成为治疗非感染性葡萄膜炎和潜在其他眼部炎症性疾病的新策略。
