Treatment of Rheumatoid Arthritis by Serum Albumin Nanoparticles Coated with Mannose to Target Neutrophils

Rheumatoid arthritis (RA) is an angiogenic and chronic inflammatory disease. One of the most extensively used first-line drugs against RA is methotrexate (MTX), but it shows poor solubility, short in vivo circulation, and off-target binding, leading to strong toxicity. To overcome these shortcomings, the present study loaded MTX into nanoparticles of human serum albumin modified with mannose (MTX-M-NPs) to target the drug to neutrophils. MTX-M-NPs were prepared, and their uptake by neutrophils was studied using laser confocal microscopy and flow cytometry. A chick chorioallantoic membrane assay was used to assess their ability to inhibit angiogenesis. The pharmacokinetics and tissue distribution of MTX-M-NPs were investigated using fluorescence microscopy and high-performance liquid chromatography. Their pharmacodynamics was evaluated in a rat model with arthritis induced by collagen. Neutrophils took up MTX-M-NPs significantly better than the same nanoparticles (NPs) without mannose. MTX-M-NPs markedly suppressed angiogenesis in chick embryos, and the MTX circulation was significantly longer when it was delivered as MTX-M-NPs than as a free drug. MTX-M-NPs accumulated mainly in arthritic joints. The retention of NPs was promoted by mannose-derived coating in arthritic joints. Serum levels of inflammatory cytokines, joint swelling, and bone erosion were significantly decreased by MTX-M-NPs. In conclusion, these NPs can prolong the in vivo circulation of MTX and target it to the sites of inflammation in RA, reducing drug toxicity. MTX-M-NPs allow the drug to exert its intrinsic anti-inflammatory, antiangiogenic, and analgesic properties, making it a useful drug delivery system in RA.