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

ABSTRACT: 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? 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? 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? siRNA (siTNF) and IL-22. Initially, we loaded siTNF into galactosylated polymeric nanoparticles (NPs). The resultant Gal-siTNF-NPs had a desirable average diameter (~261?nm), a narrow size distribution and a slightly negative surface charge (~-6?mV). These NPs successfully mediated the targeted delivery of siTNF to macrophages and efficiently inhibited the expression of TNF?. 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.

SUBMITTER: Xiao B

PROVIDER: S-EPMC6482469 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Project description:Purpose: Colitis-associated colorectal cancer (CAC) poses substantial challenges for effective treatment. Currently, there is a considerable need for the development of orally bioavailable dosage forms that enable the safe and effective delivery of therapeutic drugs to local diseased lesions in the gastrointestinal tract. Experimental Design: In this study, we developed orally deliverable nanotherapeutics for the synergistic treatment of inflammatory bowel diseases (IBDs) and CAC. Water-insoluble curcumin (CUR) and 7-ethyl-10-hydroxycamptothecin (SN38), which served as anti-inflammatory and cytotoxic agents, respectively, were chemically engineered into hydrophilic mucoadhesive chitosan for the generation of chitosan-drug amphiphiles. Results: The resulting amphiphilic constructs formed core-shell nanostructures in aqueous solutions and were orally administered for in vivo therapeutic studies. Using a preclinical CAC mouse model, we showed that the orally delivered nanotherapeutics locally accumulated in inflamed intestinal regions and tumor tissues. Furthermore, the therapeutic synergy of the combined nanotherapeutics in CAC mice was evaluated. Compared with their individual drug forms, combined CUR and SN38 nanoparticles yielded synergistic effects to alleviate intestinal inflammation and protect mice from ulcerative colitis. Notably, the combinatorial therapy demonstrated a remarkable tumor shrinkage with only ~6% of the total tumors exceeding 4 mm in diameter, whereas ~35% of tumors were observed to exceed a diameter of 4 mm in the saline-treated CAC mice. These data suggest a new and reliable approach for improving the treatment of IBD and CAC. Conclusions: Our results showed that bioadhesive chitosan materials can be used to produce colloidal-stable nanotherapeutics that are suitable for oral delivery. Both nanotherapeutics exhibited substantial accumulation in inflamed intestinal regions and tumor tissues and showed good synergy for treating CAC, warranting further clinical translation.

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

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