The Wilmer Eye Institute, School of Medicine, Johns Hopkins University, Baltimore, MD, United States; The Center for Nanomedicine, Johns Hopkins University, Baltimore, MD, United States.
The Wilmer Eye Institute, School of Medicine, Johns Hopkins University, Baltimore, MD, United States; Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
Ocul Surf. 2018 Oct;16(4):415-423. doi: 10.1016/j.jtos.2018.05.004. Epub 2018 May 16.
To investigate the efficacy of a single subconjunctival injection of dendrimer-dexamethasone conjugate in a rabbit model of induced autoimmune dacryoadenitis (AID).
Dendrimer biodistribution after subconjunctival injection in AID animals was evaluated using Cy5-labelled dendrimer (D-Cy5) and confocal microscopy. Diseased animals were treated with free dexamethasone (Free-Dex), dendrimer-dexamethasone (D-Dex), or saline via a single subconjunctival injection. The efficacy was evaluated using various clinical evaluations, such as Schirmer's test, tear breakup time (TBUT), and fluorescein and rose Bengal staining. Histopathology was evaluated by H&E staining and immunostaining. Levels of inflammatory cytokines and aquaporin proteins in the LGs were determined by real-time PCR.
Subconjunctivally administered dendrimers selectively localized in the inflamed LGs, and were taken up by the infiltrating cells. At two weeks post single dose-treatment, the D-Dex group showed improved clinical evaluations. No significant changes were observed in other groups. H&E staining demonstrated less inflammatory cell infiltration and fewer atrophic acini in D-Dex group, compared to those treated with saline or Free-Dex. Immunohistochemistry demonstrated that the intensity of CD-18 (+) and RTLA (+) was weaker in LGs in the D-Dex group than in other treatment groups. Pro-inflammatory gene expression levels of MMP9, IL6, IL8, and TNFα were significantly decreased in the D-Dex group compared to the Free-Dex and saline group.
The dendrimer exhibits pathology-dependent biodistribution in the inflamed LGs. Subconjunctivally administered D-Dex suppressed LG inflammation, leading to partial recovery of LG function with clinical improvement in induced AID. Sjögren's patients may benefit from this targeted nanomedicine approach.
研究树状大分子-地塞米松缀合物在兔诱导自身免疫性泪腺炎（AID）模型中的疗效。
使用 Cy5 标记的树状大分子（D-Cy5）和共聚焦显微镜评估 AID 动物中结膜下注射后的树状大分子分布。通过单次结膜下注射，用游离地塞米松（Free-Dex）、树突状细胞-地塞米松（D-Dex）或生理盐水治疗患病动物。使用各种临床评估，如 Schirmer 测试、泪膜破裂时间（TBUT）、荧光素和孟加拉玫瑰红染色，评估疗效。通过 H&E 染色和免疫染色评估组织病理学。通过实时 PCR 测定 LG 中炎症细胞因子和水通道蛋白的水平。
结膜下给予的树突状大分子选择性地定位于炎症 LG 中，并被浸润细胞摄取。单次剂量治疗后两周，D-Dex 组的临床评估得到改善。其他组没有观察到明显变化。与生理盐水或游离地塞米松治疗组相比，D-Dex 组的 H&E 染色显示炎症细胞浸润减少，萎缩腺泡减少。免疫组化显示，LG 中 CD-18（+）和 RTLA（+）的强度在 D-Dex 组比其他治疗组弱。与游离地塞米松和生理盐水组相比，D-Dex 组 MMP9、IL6、IL8 和 TNFα 的促炎基因表达水平显著降低。
树突状大分子在炎症 LG 中表现出依赖于病理的分布。结膜下给予 D-Dex 抑制 LG 炎症，导致 LG 功能部分恢复，诱导的 AID 临床改善。干燥综合征患者可能受益于这种靶向纳米医学方法。
