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

被引:58
作者
te Boekhorst, Bernard C. M. [1 ]
Jensen, Linda B. [2 ]
Colombo, Stefano [2 ]
Varkouhi, Amir K. [3 ]
Schiffelers, Raymond M. [3 ]
Lammers, Twan [3 ,4 ]
Storm, Gert [3 ]
Nielsen, Hanne M. [2 ]
Strijkers, Gustav J. [1 ]
Foged, Camilla [2 ]
Nicolay, Klaas [1 ]
机构
[1] Eindhoven Univ Technol, Dept Biomed Engn, NL-5600 MB Eindhoven, Netherlands
[2] Univ Copenhagen, Fac Hlth & Med Sci, Dept Pharm, DK-2100 Copenhagen O, Denmark
[3] Univ Utrecht, Fac Sci, Dept Pharmaceut, NL-3584 CA Utrecht, Netherlands
[4] Rhein Westfal TH Aachen, Dept Expt Mol Imaging, D-52074 Aachen, Germany
关键词
siRNA; RNAi; Collagen antibody induced arthritis; MRI; TNF-alpha; PLGA; SMALL INTERFERING RNA; BONE-MARROW EDEMA; RHEUMATOID-ARTHRITIS; MESSENGER-RNA; JOINT; INFLAMMATION; MACROPHAGES; GENE; QUANTIFICATION; FORMULATION;
D O I
10.1016/j.jconrel.2012.05.004
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Rheumatoid arthritis is characterized by systemic inflammation of synovial joints leading to erosion and cartilage destruction. Although efficacious anti-tumor necrosis factor a (TNF-alpha) 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-alpha in vitro and in vivo. The siRNA-loaded PLGA nanoparticles mediated a dose-dependent TNF-alpha 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-alpha siRNA (1 mu g) 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 mu g, 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. (c) 2012 Elsevier B.V. All rights reserved.
引用
收藏
页码:772 / 780
页数:9
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