Dual Functional Eudragit® S100/L30D-55 and PLGA Colon-Targeted Nanoparticles of Iridoid Glycoside for Improved Treatment of Induced Ulcerative Colitis

Chenzhe Gao,1,2,* Shen Yu,2,* Xiaonan Zhang,3 Yanxin Dang,2,4 Dan-dan Han,2 Xin Liu,2,5 Janchun Han,1 Mizhou Hui1 1Food Science College, Northeast Agricultural University, Harbin, People’s Republic of China; 2Department of Pharmaceutical Engineering, School of Materials Science and Chemical Engineering, Key Laboratory of Green Chemical Engineering in Heilongjiang Province, Harbin University of Science and Technology, Harbin, People’s Republic of China; 3College of Biological and Food Engineering, Guangdong University of Petrochemical Technology, Maoming, People’s Republic of China; 4Pharmacy Department, Fourth Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, People’s Republic of China; 5Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut, USA*These authors contributed equally to this workCorrespondence: Xin LiuDepartment of Pharmaceutical Engineering, School of Materials Science and Chemical Engineering, Key Laboratory of Green Chemical Engineering in Heilongjiang Province, Harbin University of Science and Technology, Harbin, 150040, People’s Republic of ChinaTel +86 451-86392728Fax +86 451-86392710Email xinliu98@126.comJanchun HanFood Science College, Northeast Agricultural University, Harbin, 150030, People’s Republic of ChinaTel/Fax +86 451-55190716Email hanjianchun@neau.edu.cnAim: Iridoid glycosides (IG) as the major active fraction of Syringa oblata Lindl. has a proven anti-inflammatory effect for ulcerative colitis (UC). However, its current commercial formulations are hampered by low bioavailability and unable to reach inflamed colon. To overcome the limitation, dual functional IG-loaded nanoparticles (DFNPs) were prepared to increase the residence time of IG in colon. The protective mechanism of DFNPs on DSS-induced colonic injury was evaluated in rats.Materials and Methods: We prepared DFNPs using the oil-in-water emulsion method. PLGA was selected as sustained-release polymer, and ES100 and EL30D-55 as pH-responsive polymers. The morphology and size distribution of NPs were measured by SEM and DLS technique. To evaluate colon targeting of DFNPs, DiR, was encapsulated as a fluorescent probe into NPs. Fluorescent distribution of NPs were investigated. The therapeutic potential and in vivo transportation of NPs in gastrointestinal tract were evaluated in a colitis model.Results: SEM images and zeta data indicated the successful preparation of DFNPs. This formulation exhibited high loading capacity. Drug release results suggested DFNPs released less than 20% at the first 6 h in simulated gastric fluid (pH1.2) and simulated small intestine fluid (pH6.8). A high amount of 84.7% sustained release from NPs in simulated colonic fluid (pH7.4) was beyond 24 h. DiR-loaded NPs demonstrated a much higher colon accumulation, suggesting effective targeting due to functionalization with pH and time-dependent polymers. DFNPs could significantly ameliorate the colonic damage by reducing DAI, macroscopic score, histological damage and cell apoptosis. Our results also proved that the potent anti-inflammatory effect of DFNPs is contributed by decrease of NADPH, gene expression of COX-2 and MMP-9 and the production of TNF-α, IL-17, IL-23 and PGE2.Conclusion: We confirm that DFNPs exert protective effects through inhibiting the inflammatory response, which could be developed as a potential colon-targeted system.Keywords: iridoid glycoside, ulcerative colitis, Syringa oblata Lindl., pH-sensitive and time-dependent, colon-targeted nanoparticles