Journal
JOURNAL OF CONTROLLED RELEASE
Volume 287, Issue -, Pages 235-246Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2018.08.021
Keywords
TNF alpha silencing; Interleukin-22; Oral administration; Targeted nanoparticle; Ulcerative colitis; Combination therapy
Funding
- National Institutes of Health of Diabetes and Digestive and Kidney [RO1DK116306, RO1DK107739, RO1DK071594]
- Litwin IBD Pioneers initiative
- National Natural Science Foundation of China [51503172, 81571807]
- Department of Veterans Affairs [BX002516]
- Fundamental Research Funds for the Central Universities [XDJK2017B058]
- Young Core Teacher Program of the Municipal Higher Educational Institution of Chongqing
- State Key Laboratory of Silkworm Genome Biology
- Senior Research Career Scientist Award from the Department of Veterans Affairs
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Pro-resolving factors that are critical for colonic epithelial restitution were down-regulated during the treatment with inhibitor of pro-inflammatory cytokines (e.g., anti-TNF alpha antibody) in ulcerative colitis (UC) therapy. We hypothesized that increased amounts of factors such as interleukin-22 (IL-22) during the therapeutic inhibition of TNF alpha could facilitate the resolution of intestinal inflammation. As combination therapy is an emerging strategy for UC treatment, we attempt to treat established UC based on the combination of TNF alpha siRNA (siTNF) and IL-22. Initially, we loaded siTNF into galactosylated polymeric nanoparticles (NPs). The resultant Gal-siTNF-NPs had a desirable average diameter (similar to 261 nm), a narrow size distribution and a slightly negative surface charge (similar to -6 mV). These NPs successfully mediated the targeted delivery of siTNF to macrophages and efficiently inhibited the expression of TNF alpha. Meanwhile, IL-22 could obviously accelerate mucosal healing. More importantly, oral administration of Gal-siTNF-NPs plus IL-22 embedded in a hydrogel (chitosan/alginate) showed much stronger capacities to down-regulate the expression of pro-inflammatory factors and promote mucosal healing. This formulation also yielded a much better therapeutic efficacy against UC in a mouse model compared to hydrogel loaded with Gal-siTNF-NPs or IL-22 alone. Our results strongly demonstrate that Gal-siTNF-NP/IL-22-embedded hydrogel can target to inflamed colon, and co-deliver siTNF and IL-22 to boost the effects of either monotherapy, which may become a promising oral drug formulation and enable targeted combination therapy of UC.
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