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

Ulcerativecolitis (UC) is a chronic inflammatory boweldiseaseof unknown etiology affecting the colon and rectum. Current therapeuticsare focused on suppressing inflammation but are ineffective. Combininganti-inflammatory therapeutic approaches with pro-resolution mightbe a superior strategy for UC treatment. Andrographolide (AG), anactive 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 inflammatoryresolution. Herein, we developed a dextran-functionalized PLGA nanocarrierfor 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, slowdrug release, efficient targeting, and biodegradability. The resultingnanocarrier had a nano-scaled diameter of & SIM;200 nm and a sphericalshape. After being coated with dextran (Dex), the resulting AG/CORM-2@NP-Dexcould be efficiently internalized by Colon-26 and Raw 264.7 cells in vitro and preferentially localized to the inflamed colonwith chitosan/alginate hydrogel protection by gavage. AG/CORM-2@NP-Dexperformed anti-inflammatory effects by eliminating the over-productionof pro-inflammatory mediator, nitric oxide (NO), and down-regulatingthe expression of pro-inflammatory cytokines (TNF-& alpha;, IL-1 & beta;and IL-6), while it showed pro-resolving function by acceleratingM1 to M2 macrophage conversion and up-regulating resolution-relatedgenes (IL-10, TGF-& beta;, and HO-1). In the colitis model, oral administrationof AG/CORM-2@NP-Dex in a chitosan/alginate hydrogel also showed synergisticallyanti-inflammatory/pro-resolving effects, therefore relieving UC effectively.Without appreciable systemic toxicity, this bifunctional nanocarrierrepresents a novel therapeutic approach for UC and is expected toachieve long-term inflammatory remission.