溃疡性结肠炎(UC)是一种病因不明的慢性炎症性肠病,累及结肠和直肠。目前的疗法集中于抑制炎症,但无效。将抗炎治疗方法与前分辨率相结合可能是UC治疗的优越策略。穿心莲内酯(AG),一种来自穿心莲植物的活性化合物,在各种炎性疾病中表现出抗炎作用。气态介质,如一氧化碳(CO),在炎症消退中起作用。在这里,我们开发了一种葡聚糖功能化的PLGA纳米载体,用于有效递送AG和一氧化碳供体(CORM-2),用于基于具有良好生物相容性的PLGA的UC(AG/CORM-2@NP-Dex)的协同抗炎/促解治疗。缓慢的药物释放,有效的瞄准,和生物降解性。所得纳米载体具有〜200nm的纳米级直径和球形。涂上葡聚糖(Dex)后,所得的AG/CORM-2@NP-Dex可以在体外被Colon-26和Raw264.7细胞有效内化,并通过管饲法保护壳聚糖/藻酸盐水凝胶优先定位于发炎的结肠。AG/CORM-2@NP-Dex通过消除促炎介质的过度产生来发挥抗炎作用,一氧化氮(NO),并下调促炎细胞因子(TNF-α,IL-1β和IL-6),同时通过加速M1到M2巨噬细胞的转化和上调分辨率相关基因(IL-10,TGF-β,和HO-1)。在结肠炎模型中,在壳聚糖/藻酸盐水凝胶中口服AG/CORM-2@NP-Dex也显示出协同抗炎/促解作用,因此有效缓解UC。没有明显的全身毒性,这种双功能纳米载体代表了一种新的UC治疗方法,有望实现长期炎症缓解.
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.