Natural-lipid nanoparticle-based therapeutic approach to deliver 6-shogaol and its metabolites M2 and M13 to the colon to treat ulcerative colitis

• Published in: Journal of controlled release Vol. 323; pp. 293 - 310
• Main Authors: Yang, Chunhua, Zhang, Mingzhen, Lama, Sudeep, Wang, Lixin, Merlin, Didier
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.07.2020
• Subjects: 6-shogaol; animal models; Animals; anti-inflammatory activity; anti-inflammatory agents; bioavailability; Caco-2 Cells; Catechols; Colitis - chemically induced; Colitis - drug therapy; Colitis, Ulcerative - drug therapy; Colon; Colon targeted drug delivery; Dextran Sulfate; Disease Models, Animal; drug delivery systems; gene expression regulation; Humans; in vitro studies; interleukin-10; interleukin-1beta; interleukin-6; kidneys; Lipids; liver; macrophages; metabolites; mice; Nanoparticles; Natural-lipid nanoparticles; oral administration; pharmacokinetics; Phase II metabolites; reverse transcriptase polymerase chain reaction; tissue repair; tumor necrosis factor-alpha; ulcerative colitis; Natural-lipid nanoparticles; Colon targeted drug delivery; 6-shogaol; Phase II metabolites
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2020.04.032

The anti-inflammatory drug candidate, 6-shogaol, has demonstrated excellent efficacies in various in vitro studies. However, its rapid metabolism after oral administration results in poor bioavailability and undetectable in vivo pharmacokinetics. Here, we constructed a natural-lipid (NL) nanoparticle drug delivery system (NP-DDS) to encapsulate 6-shogaol and undertake its controlled release to the proposed drug target (colon). Our in vitro drug-release assay revealed that NL-encapsulated 6-shogaol (6-S-NL) exhibits a delayed drug-release profile compared to free 6-shogaol (free-6-S). Consistent with our expectations, orally administrated 6-S-NL exhibits a superior anti-inflammatory efficacy likely due to the controlled release compared to free 6-S in a dextran sulfate sodium (DSS)-induced mouse model of colitis. Although 6-S-NL treatment yields an enhanced concentration of 6-shogaol at the target site (colon), this concentration is still far below the effective level. We hypothesize that the released 6-shogaol undergoes rapid metabolism and that the metabolites of 6-shogaol may contribute to the anti-inflammatory efficacy of 6-S-NL. We thus examined the in vitro anti-inflammatory efficacies of two highly abundant colonic metabolites, M2 (a cysteine-conjugated metabolite) and M13 (a glutathione-conjugated metabolite), against macrophage cells. Reverse transcription-polymerase chain reaction (RT-PCR) data showed that both M2 and M13 (at 1.0 μg/mL) could down-regulate pro-inflammatory factors (TNF-α, IL-1β, and IL-6) and up-regulate an anti-inflammatory factor (IL-10) in inflamed Raw 264.7 cells. Subsequent in vitro wound-healing assays also confirmed that M2 and M13 accelerate the wound recovery process of Caco-2 cells at the concentrations seen in the colon (1.0 μg/mL). Further, in the DSS-induced mouse model of colitis, oral administration of M2- or M13-loaded NL nanoparticles (M2-NL, M13-NL) demonstrated excellent in vivo wound-healing effects, and these activities were better than those observed for 6-S-NL. Combined with the 6-S-NL's bio-distribution assay, our data show that: the 6-shogaol metabolites, M2 and M13, are more potent anti-inflammatory compounds than 6-shogaol itself; NL nanoparticles can effectively deliver 6-shogaol to the colon, with little accumulation seen in the kidney or liver; and the actions of M2 and M13 mostly confer the anti-inflammatory effect of 6-S-NL. Our results explained the discrepancy between the low tissue concentrations of NL delivered 6-shogaol and its effectiveness against ulcerative colitis (UC) in a mouse model. This study paved the way for further developing the NL-loaded active metabolites, M2 or M13, as novel targeted therapeutic approaches for curing UC. Natural-lipid nanoparticle encapsulation significantly increases the bio-distribution of 6-shogaol and its metabolites M2 and M13 to the colon. [Display omitted]