Oral Nanotherapeutics of Andrographolide/Carbon Monoxide Donor for Synergistically Anti-inflammatory and Pro-resolving Treatment of Ulcerative Colitis.

Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology affecting the colon and rectum. Current therapeutics are focused on suppressing inflammation but are ineffective. Combining anti-inflammatory therapeutic approaches with pro-resolution might be a superior strategy for UC treatment. Andrographolide (AG), an active compound from the plant Andrographis paniculata, presented anti-inflammatory effects in various inflammatory diseases. Gaseous mediators, such as carbon monoxide (CO), have a role in inflammatory resolution. Herein, we developed a dextran-functionalized PLGA nanocarrier for efficient delivery of AG and a carbon monoxide donor (CORM-2) for synergistically anti-inflammatory/pro-resolving treatment of UC (AG/CORM-2@NP-Dex) based on PLGA with good biocompatibility, slow drug release, efficient targeting, and biodegradability. The resulting nanocarrier had a nano-scaled diameter of ∼200 nm and a spherical shape. After being coated with dextran (Dex), the resulting AG/CORM-2@NP-Dex could be efficiently internalized by Colon-26 and Raw 264.7 cells in vitro and preferentially localized to the inflamed colon with chitosan/alginate hydrogel protection by gavage. AG/CORM-2@NP-Dex performed anti-inflammatory effects by eliminating the over-production of pro-inflammatory mediator, nitric oxide (NO), and down-regulating the expression of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), while it showed pro-resolving function by accelerating M1 to M2 macrophage conversion and up-regulating resolution-related genes (IL-10, TGF-β, and HO-1). In the colitis model, oral administration of AG/CORM-2@NP-Dex in a chitosan/alginate hydrogel also showed synergistically anti-inflammatory/pro-resolving effects, therefore relieving UC effectively. Without appreciable systemic toxicity, this bifunctional nanocarrier represents a novel therapeutic approach for UC and is expected to achieve long-term inflammatory remission.