Targeted delivery of morin, a dietary bioflavanol encapsulated mannosylated liposomes to the macrophages of adjuvant-induced arthritis rats inhibits inflammatory immune response and osteoclastogenesis

• Published in: European journal of pharmaceutics and biopharmaceutics 2017-06, Vol.115, p.229-242
• Main Authors: Sultana, Farhath, Neog, Manoj Kumar, Rasool, MahaboobKhan
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Experimental - drug therapy; Arthritis, Rheumatoid - drug therapy; Cytokines - metabolism; Diet - methods; Female; Flavonoids - administration & dosage; Flavonoids - chemistry; Inflammation - drug therapy; Inflammation - metabolism; Inflammation Mediators - metabolism; Liposomes - administration & dosage; Liposomes - chemistry; Macrophages; Macrophages - drug effects; Male; Mannose - administration & dosage; Mannose - chemistry; Morin; Morin encapsulated mannosylated liposomes; Osteoclastogenesis; Osteogenesis - drug effects; Rats; Rats, Wistar; Transcription Factor RelA - metabolism; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2017.03.009

[Display omitted] The purpose of the study was to develop a liposomal drug delivery system for morin, a dietary polyphenol, in order to target the synovial macrophages and investigate the remission of disease severity in the adjuvant-induced arthritic (AIA) rats. To do so, mannose decorated liposomal morin (ML-Morin) was prepared using the thin film hydration method and the physicochemical properties were characterized. The particle size and zeta potential of liposomal morin (L-Morin) was found to be 127.9nm±2.6 and −24.5mV±0.76, whereas ML-Morin showed an increased value of 132.5nm±5.2 and −54.8mV±0.67 respectively. Further, the drug entrapment efficiency (% EE) of ML-Morin was found 86.7±3.8%. To understand the efficacy of L-Morin, ML-Morin over free-Morin; cellular uptake, production and expression of pro-inflammatory mediators, osteoclastogenic factors, and transcription factors were evaluated in primarily isolated synovial and spleen macrophages. Interestingly, confocal microscopic images showed an increased uptake of ML-Morin in the synovial and spleen macrophages than L-morin. In addition, ML-Morin significantly suppressed the production and mRNA expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-17), angiogenic factors (VEGF), an inflammatory enzyme (iNOS), and transcription factor (NF-κB-p65). Furthermore, the protein expression of TNF-α, IL-1β, IL-6, IL-17, RANKL, STAT-3, and p-STAT-3 was found to decrease with increased osteoprotegerin (OPG) expression in the ML-Morin targeted macrophages. Thus, our findings endorsed that, ML-Morin preferential internalization into the macrophages of arthritic rats effectively inhibited the inflammatory immune response and osteoclastogenesis better than the dexamethasone palmitate encapsulated mannosylated liposomes (ML-DP), a reference drug as evidenced by clinical and histological analysis.