Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, Los Angeles, USA.
J Control Release. 2013 Nov 10;171(3):269-79. doi: 10.1016/j.jconrel.2013.07.016. Epub 2013 Jul 25.
Sjögren's syndrome (SjS) is a chronic autoimmune disease characterized initially by lymphocytic infiltration and destruction of exocrine glands, followed by systemic organ damage and B-cell lymphoma. Conventional treatment is based on management of symptoms and there is a shortage of therapies that address the underlying causes of inflammation at source exocrine tissue. The aim of this study was to test a novel protein polymer-based platform consisting of diblock copolymers composed from Elastin-like Polypeptides (ELPs) fused with FKBP12, to deliver a potent immunosuppressant with dose-limiting toxicity, rapamycin (Rapa) also known as Sirolimus, and evaluate its effects on the inflamed lacrimal gland (LG) of non-obese diabetic mouse (NOD), a classic mouse model of SjS. Both soluble and diblock copolymer ELPs were fused to FKBP12 and characterized with respect to purity, hydrodynamic radii, drug entrapment and release. Both formulations showed successful association with Rapa; however, the nanoparticle formulation, FSI, released drug with nearly a 5 fold longer terminal half-life of 62.5h. The strong interaction of FSI nanoparticles with Rapa was confirmed in vivo by a shift in the monoexponential pharmacokinetic profile for free drug to a biexponential profile for the nanoparticle formulation. When acutely administered by injection into NOD mice via the tail vein, this FSI formulation significantly suppressed lymphocytic infiltration in the LG relative to the control group while reducing toxicity. There was also a significant effect on inflammatory and mammalian target of Rapamycin (mTOR) pathway genes in the LG and surprisingly, our nanoparticle formulation was significantly better at decreasing a proposed tear biomarker of SjS, cathepsin S (CATS) compared to free drug. These findings suggest that FSI is a promising tool for delivering Rapa for treatment of SjS in a murine model and may be further explored to meet the unmet medical challenge of SjS.
干燥综合征（SjS）是一种慢性自身免疫性疾病，最初表现为淋巴细胞浸润和外分泌腺破坏，随后出现全身器官损伤和 B 细胞淋巴瘤。传统的治疗方法基于症状的管理，缺乏针对外分泌组织炎症根本原因的治疗方法。本研究旨在测试一种新型的蛋白聚合物平台，该平台由弹性蛋白样多肽（ELP）组成的嵌段共聚物组成，融合了 FKBP12，以输送具有剂量限制毒性的强效免疫抑制剂雷帕霉素（Rapa），也称为西罗莫司，并评估其对非肥胖型糖尿病小鼠（NOD）的炎症性泪腺（LG）的影响，NOD 是 SjS 的经典小鼠模型。可溶性和嵌段共聚物 ELP 均与 FKBP12 融合，并对纯度、流体力学半径、药物包封和释放进行了表征。两种制剂均成功地与 Rapa 结合；然而，纳米粒子制剂 FSI 的药物释放半衰期几乎延长了 5 倍，达到 62.5h。体内实验证实了 FSI 纳米粒子与 Rapa 的强相互作用，使游离药物的单指数药代动力学曲线转变为纳米粒子制剂的双指数曲线。当通过尾静脉注射急性给予 NOD 小鼠时，与对照组相比，这种 FSI 制剂显著抑制了 LG 中的淋巴细胞浸润，同时降低了毒性。LG 中的炎症和哺乳动物雷帕霉素靶蛋白（mTOR）通路基因也有显著影响，令人惊讶的是，与游离药物相比，我们的纳米粒子制剂在降低 SjS 的一个拟议的泪液生物标志物——组织蛋白酶 S（CATS）方面效果更显著。这些发现表明，FSI 是一种有前途的工具，可用于在小鼠模型中输送 Rapa 治疗 SjS，并可能进一步探索以满足 SjS 未满足的医疗挑战。
