MRI-assessed therapeutic effects of locally administered PLGA nanoparticles loaded with anti-inflammatory siRNA in a murine arthritis model
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MRI-assessed therapeutic effects of locally administered PLGA nanoparticles loaded with anti-inflammatory siRNA in a murine arthritis model. / Te Boekhorst, Bernard C M; Jensen, Linda B; Colombo, Stefano; Varkouhi, Amir K; Schiffelers, Raymond M; Lammers, Twan; Storm, Gert; Nielsen, Hanne M; Strijkers, Gustav J; Foged, Camilla; Nicolay, Klaas.
In: Journal of controlled release : official journal of the Controlled Release Society, Vol. 161, No. 3, 2012, p. 772-80.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - MRI-assessed therapeutic effects of locally administered PLGA nanoparticles loaded with anti-inflammatory siRNA in a murine arthritis model
AU - Te Boekhorst, Bernard C M
AU - Jensen, Linda B
AU - Colombo, Stefano
AU - Varkouhi, Amir K
AU - Schiffelers, Raymond M
AU - Lammers, Twan
AU - Storm, Gert
AU - Nielsen, Hanne M
AU - Strijkers, Gustav J
AU - Foged, Camilla
AU - Nicolay, Klaas
N1 - Copyright © 2012 Elsevier B.V. All rights reserved.
PY - 2012
Y1 - 2012
N2 - Rheumatoid arthritis is characterized by systemic inflammation of synovial joints leading to erosion and cartilage destruction. Although efficacious anti-tumor necrosis factor a (TNF-a) 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-a in vitro and in vivo. The siRNA-loaded PLGA nanoparticles mediated a dose-dependent TNF-a 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-a siRNA (1µg) 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 10µg, 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.
AB - Rheumatoid arthritis is characterized by systemic inflammation of synovial joints leading to erosion and cartilage destruction. Although efficacious anti-tumor necrosis factor a (TNF-a) 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-a in vitro and in vivo. The siRNA-loaded PLGA nanoparticles mediated a dose-dependent TNF-a 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-a siRNA (1µg) 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 10µg, 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.
U2 - 10.1016/j.jconrel.2012.05.004
DO - 10.1016/j.jconrel.2012.05.004
M3 - Journal article
C2 - 22580113
VL - 161
SP - 772
EP - 780
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
IS - 3
ER -
ID: 40378494