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

• Published in: Journal of controlled release 2012-08, Vol.161 (3), p.772-780
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; anti-inflammatory activity; Arthritis, Experimental - pathology; Arthritis, Experimental - therapy; Arthritis, Rheumatoid - pathology; Arthritis, Rheumatoid - therapy; Biological and medical sciences; bone marrow; Bone Marrow - drug effects; Bone Marrow - pathology; cartilage; Cell Line; collagen; Collagen antibody induced arthritis; dose response; Drug Carriers - administration & dosage; edema; Fatty Acids, Monounsaturated - administration & dosage; Femur; Gene Silencing; General pharmacology; inflammation; Lactic Acid - administration & dosage; Magnetic Resonance Imaging; Male; Medical sciences; Mice; Mice, Inbred DBA; MRI; nanoparticles; Nanoparticles - administration & dosage; necrosis; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; PLGA; Polyglycolic Acid - administration & dosage; Quaternary Ammonium Compounds - administration & dosage; remission; rheumatoid arthritis; RNA, Small Interfering - administration & dosage; RNAi; siRNA; small interfering RNA; therapeutics; Tibia; TNF-α; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - genetics
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2012.05.004

Rheumatoid arthritis is characterized by systemic inflammation of synovial joints leading to erosion and cartilage destruction. Although efficacious anti-tumor necrosis factor α (TNF-α) 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-α in vitro and in vivo. The siRNA-loaded PLGA nanoparticles mediated a dose-dependent TNF-α 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-α 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. Intra-articular treatment with TNF-α siRNA-loaded PLGA nanoparticles mediated a significant and specific reduction in visual paw scores and MRI-quantified joint effusion at 1μg siRNA. [Display omitted]