TNFα gene silencing mediated by orally targeted nanoparticles combined with interleukin-22 for synergistic combination therapy of ulcerative colitis

JOURNAL OF CONTROLLED RELEASE

卷:287

Article

Xiao, Bo^1,2  Chen, Qiubing¹  Zhang, Zhan²  Wang, Lixin^2,3  Kang, Yuejun¹  Denning, Timothy²  Merlin, Didier^2,3 

[1] Southwest Univ, Inst Clean Energy & Adv Mat, Fac Mat & Energy, Chongqing 400715, Peoples R China

[2] Georgia State Univ, Ctr Diagnost & Therapeut, Inst Biomed Sci, Digest Dis Res Grp, Atlanta, GA 30302 USA

[3] Atlanta Vet Affairs Med Ctr, Decatur, GA 30033 USA

关键词: TNF alpha silencing;    Interleukin-22;    Oral administration;    Targeted nanoparticle;    Ulcerative colitis;    Combination therapy;   

DOI  :  10.1016/j.jconrel.2018.08.021

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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