Novel DEK-Targeting Aptamer Delivered by a Hydrogel Microneedle Attenuates Collagen-Induced Arthritis
Inflammation
Oncogene Proteins
0303 health sciences
Anti-Inflammatory Agents
Hydrogels
Aptamers, Nucleotide
Protective Agents
Arthritis, Experimental
Extracellular Traps
Cell Line
3. Good health
Arthritis, Rheumatoid
DNA-Binding Proteins
Mice
03 medical and health sciences
Cartilage
RAW 264.7 Cells
Human Umbilical Vein Endothelial Cells
Animals
Humans
Collagen
Poly-ADP-Ribose Binding Proteins
DOI:
10.1021/acs.molpharmaceut.0c00954
Publication Date:
2020-11-30T23:39:27Z
AUTHORS (8)
ABSTRACT
DEK protein is critical to the formation of neutrophil extracellular traps (NETs) in rheumatoid arthritis (RA). Blocking DEK using the aptamer DTA via articular injection has been shown to have robust anti-inflammatory efficacy in a previous study. However, DTA is prone to nuclease degradation and renal clearance in vivo. RA is a systemic disease that involves multiple joints, and local injection is impractical in clinical settings. In this study, DTA was modified with methoxy groups on all deoxyribose sugar units and inverted deoxythymidine on the 3' end (DTA4) to enhance its stability against nuclease. DTA4 is stable for 72 h in 90% mouse serum and maintains a high binding affinity to DEK. DTA4 effectively inhibits the formation of NETs and the migration of HUVECs in vitro. DTA4 was then modified with cholesterol on its 5' end to form DTA6. DTA6 dramatically reduces DEK expression in inflammatory RAW264.7 cells. A hydrogel microneedle (hMN) was then fabricated for the transdermal delivery of DTA6. The hMN maintains morphological integrity after absorbing the aptamer solution, effectively pierces the skin, and rapidly releases DTA6 into the dermis. The DTA6-loaded hMN significantly attenuates inflammation and protects joints from cartilage/bone erosion in collagen-induced arthritis (CIA) mice.
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