MRI-assessed therapeutic effects of locally administered PLGA nanoparticles loaded with anti-inflammatory siRNA in a murine arthritis model

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• 作者：Bernard C.M. te Boekhorst ; Linda B. Jensen ; Stefano Colombo ; Amir K. Varkouhi ; Raymond M. Schiffelers ; Twan Lammers ; Gert Storm ; Hanne M. Nielsen ; Gustav J. Strijkers ; Camilla Foged ; Klaas Nicolay
• 关键词：siRNA ; RNAi ; Collagen antibody induced arthritis ; MRI ; TNF-¦Á ; PLGA
• 刊名：Journal of Controlled Release
• 出版年：2012
• 出版时间：10 August, 2012
• 年：2012
• 卷：161
• 期：3
• 页码：772-780
• 全文大小：749 K

文摘

Rheumatoid arthritis is characterized by systemic inflammation of synovial joints leading to erosion and cartilage destruction. Although efficacious anti-tumor necrosis factor ¦Á (TNF-¦Á) biologic therapies exist, there is an unmet medical need for safe and more efficient treatment regimens for disease remission. We evaluated the anti-inflammatory effects of poly(dl-lactide-co-glycolide acid) (PLGA) nanoparticles loaded with small interfering RNA (siRNA) directed against TNF-¦Á in vitro and in vivo. The siRNA-loaded PLGA nanoparticles mediated a dose-dependent TNF-¦Á silencing in lipopolysaccharide-activated RAW 264.7 cells in vitro. The severity of collagen antibody-induced arthritis in DBA/1J mice was assessed by paw scoring and compared to the degree of magnetic resonance imaging (MRI)-quantified joint effusion and bone marrow edema. Two intra-articular treatments per joint with nanoparticles loaded with TNF-¦Á siRNA (1 ¦Ìg) resulted in a reduction in disease activity, evident by a significant decrease of the paw scores and joint effusions, as compared to treatment with PLGA nanoparticles loaded with non-specific control siRNA, whereas the degree of bone marrow edema in the tibial and femoral head remained unchanged. When the siRNA dose was 5 or 10 ¦Ìg, there was no difference between the specific and the non-specific siRNA treatment groups. These findings suggest that MRI is a promising method for evaluation of early disease progression and treatment in murine arthritis models. In addition, proper siRNA dosing seems to be important for a positive therapeutic outcome in vivo. However, further studies are needed to fully clarify the mechanism(s) underlying the observed anti-inflammatory effects of the siRNA-loaded nanoparticles.