TNF-α Gene Silencing Using Polymerized siRNA/Thiolated Glycol Chitosan Nanoparticles for Rheumatoid Arthritis
TNF-α Gene Silencing Using Polymerized siRNA/Thiolated Glycol Chitosan Nanoparticles for Rheumatoid Arthritis
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DOI：
10.1038/mt.2013.245
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发表时间：
2014-02-01
影响因子：
12.4
通讯作者：
Kim, Kwangmeyung
中科院分区：
文献类型：
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作者：
Lee, So Jin;Lee, Aeju;Kim, Kwangmeyung
在参与类风湿关节炎（RA）发病的各种促炎因子中，肿瘤坏死因子(TNF)- α在其他细胞因子的释放和慢性炎症的诱导中起着关键作用。尽管siRNA具有治疗潜力，但由于其在生理液体中的稳定性较差，因此将其递送到靶细胞中存在挑战。在此，我们设计了一种靶向tnf - α的巯基化的聚合siRNA纳米复合物（polysirna）。乙二醇壳聚糖（tGC）聚合物治疗RA。Poly-siRNA是通过siRNA正链和反义链5′端巯基的自聚合制备而成，并包封在tGC聚合物中，得到平均直径为370 nm的Poly-siRNA -tGC纳米颗粒（psi-tGC-NPs）。在巨噬细胞培养系统中，psi-tGC-NPs表现出快速的细胞摄取和出色的体外TNF-a基因沉默效果。重要的是，psi-tGC-NPs在胶原诱导关节炎（CIA）小鼠的关节部位显示出高蓄积。基质金属蛋白酶3特异性纳米探针和显微计算机断层扫描获得的治疗监测数据显示，静脉注射psi-tGC-NPs可显著抑制CIA小鼠的炎症和骨侵蚀，其效果与甲氨喋呤（5 mg/kg）相当。因此，针对特定细胞因子的psi-tGC-NP疗法的可用性可能预示着RA治疗的新时代。
Among various proinflammatory cytokines involved in the pathogenesis of rheumatoid arthritis (RA), tumor necrosis factor (TNF)-alpha, plays a pivotal role in the release of other cytokines and induction of chronic inflammation. Even though siRNA has the therapeutic potential, they have a challenge to be delivered into the target cells because of their poor stability in physiological fluids. Herein, we design a nanocomplex of polymerized siRNA (poly-siRNA) targeting TNF-alpha with thiolated. glycol chitosan (tGC) polymers for the treatment of RA. Poly-siRNA is prepared through self-polymerization of thiol groups at the 5' end of sense and antisense strand of siRNA and encapsulated into tGC polymers, resulting in poly-siRNA-tGC nanoparticles (psi-tGC-NPs) with an average diameter of 370 nm. In the macrophage culture system, psi-tGC-NPs exhibit rapid cellular uptake and excellent in vitro TNF-a gene silencing efficacy. Importantly, psi-tGC-NPs show the high accumulation at the arthritic joint sites in collagen-induced arthritis (CIA) mice. Treatment monitoring data obtained by the matrix metalloproteinase 3 specific nanoprobe and microcomputed tomography show that intravenous injection of psi-tGC-NPs significantly inhibits inflammation and bone erosion in CIA mice, comparable to methotrexate (5 mg/kg). Therefore, the availability of psi-tGC-NP therapy that target specific cytokines may herald new era in the treatment of RA.