在以干燥综合征为特征的自身免疫性泪腺炎小鼠模型中，泪道内持续递送雷帕霉素显示出无全身毒性的治疗效果,Biomacromolecules

当前位置： X-MOL 学术 › Biomacromolecules › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

在以干燥综合征为特征的自身免疫性泪腺炎小鼠模型中，泪道内持续递送雷帕霉素显示出无全身毒性的治疗效果
Biomacromolecules ( IF 5.5 ) Pub Date : 2020-12-27 , DOI: 10.1021/acs.biomac.0c01468
Yaping Ju ₁ , Maria C Edman ₂ , Hao Guo ₁ , Srikanth Reddy Janga ₂ , Santosh Peddi ₁ , Stan G Louie ₃ , Jason A Junge ₄ , J Andrew MacKay _{1,

2,

5} , Sarah F Hamm-Alvarez _{1,

2}

Affiliation

干燥综合征 (SS) 是一种与严重外分泌病相关的自身免疫性疾病，其特征是严重的淋巴细胞浸润（泪腺炎）和产生泪液的泪腺 (LGs) 功能丧失。全身给药雷帕霉素 (Rapa) 可显着降低 SS 相关自身免疫性泪腺炎的男性非肥胖糖尿病 (NOD) 模型中的 LG 炎症。然而，这种强效免疫抑制剂的全身毒性限制了其应用。作为替代方案，本文报道了一种使用由热响应弹性蛋白样多肽 (ELP) 和 Rapa (5FV) 的同源受体 FKBP 组成的贮库制剂的 LG 内递送方法。使用清除组织并通过激光扫描共聚焦和光片显微镜观察，在切除的整个 LG 中确认了仓库的形成。在 NOD 小鼠疾病模型中评估了 LG 仓库的安全性、有效性和 LG 内药代动力学。与与可溶性载体对照 (5FA) 复合的 Rapa 递送相比，使用长效制剂 (5FV) 的 LG 内注射在 LG 中保留 Rapa 的平均停留时间 (MRT) 为 75.6 小时，后者的 MRT 为 11.7 小时。 LG。与连续 2 周（七剂）每隔一天全身给药 Rapa 相比，代表总药物量少 16 倍的单一 LG 内 Rapa 贮库足以抑制 LG 炎症并改善泪液产生。这种治疗方式进一步降低了高血糖和高脂血症的标志物，同时没有显示 LG 坏死或纤维化的证据。这种方法代表了一种潜在的治疗 SS 相关的自身免疫性泪腺炎的新疗法，可适用于其他炎症部位的局部给药；此外，这些发现揭示了光学成像在监测局部给药治疗处置方面的实用性。

"点击查看英文标题和摘要"

Intralacrimal Sustained Delivery of Rapamycin Shows Therapeutic Effects without Systemic Toxicity in a Mouse Model of Autoimmune Dacryoadenitis Characteristic of Sjögren’s Syndrome

Sjögren’s syndrome (SS) is an autoimmune disease associated with severe exocrinopathy, which is characterized by profound lymphocytic infiltration (dacryoadenitis) and loss of function of the tear-producing lacrimal glands (LGs). Systemic administration of Rapamycin (Rapa) significantly reduces LG inflammation in the male Nonobese Diabetic (NOD) model of SS-associated autoimmune dacryoadenitis. However, the systemic toxicity of this potent immunosuppressant limits its application. As an alternative, this paper reports an intra-LG delivery method using a depot formulation comprised of a thermoresponsive elastin-like polypeptide (ELP) and FKBP, the cognate receptor for Rapa (5FV). Depot formation was confirmed in excised whole LG using cleared tissue and observation by both laser-scanning confocal and lightsheet microscopy. The LG depot was evaluated for safety, efficacy, and intra-LG pharmacokinetics in the NOD mouse disease model. Intra-LG injection with the depot formulation (5FV) retained Rapa in the LG for a mean residence time (MRT) of 75.6 h compared to Rapa delivery complexed with a soluble carrier control (5FA), which had a MRT of 11.7 h in the LG. Compared to systemic delivery of Rapa every other day for 2 weeks (seven doses), a single intra-LG depot of Rapa representing 16-fold less total drug was sufficient to inhibit LG inflammation and improve tear production. This treatment modality further reduced markers of hyperglycemia and hyperlipidemia while showing no evidence of necrosis or fibrosis in the LG. This approach represents a potential new therapy for SS-related autoimmune dacryoadenitis, which may be adapted for local delivery at other sites of inflammation; furthermore, these findings reveal the utility of optical imaging for monitoring the disposition of locally administered therapeutics.

更新日期：2020-12-27

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南