James Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
James Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
Mol Ther. 2014 Mar;22(3):522-534. doi: 10.1038/mt.2013.190. Epub 2013 Aug 13.
The gut mucosal immune system is considered to play an important role in counteracting potential adverse effects of food-derived antigens including nanovesicles. Whether nanovesicles naturally released from edible fruit work in a coordinated manner with gut immune cells to maintain the gut in a noninflammatory status is not known. Here, as proof of concept, we demonstrate that grapefruit-derived nanovesicles (GDNs) are selectively taken up by intestinal macrophages and ameliorate dextran sulfate sodium (DSS)-induced mouse colitis. These effects were mediated by upregulating the expression of heme oxygenase-1 (HO-1) and inhibiting the production of IL-1β and TNF-α in intestinal macrophages. The inherent biocompatibility and biodegradability, stability at wide ranges of pH values, and targeting of intestinal macrophages led us to further develop a novel GDN-based oral delivery system. Incorporating methotrexate (MTX), an anti-inflammatory drug, into GDNs and delivering the MTX-GDNs to mice significantly lowered the MTX toxicity when compared with free MTX, and remarkably increased its therapeutic effects in DSS-induced mouse colitis. These findings demonstrate that GDNs can serve as immune modulators in the intestine, maintain intestinal macrophage homeostasis, and can be developed for oral delivery of small molecule drugs to attenuate inflammatory responses in human disease.
肠道黏膜免疫系统被认为在对抗食物来源的抗原（包括纳米囊泡）的潜在不良反应方面发挥着重要作用。目前尚不清楚食用水果自然释放的纳米囊泡是否与肠道免疫细胞协同作用，以维持肠道非炎症状态。在这里，作为概念验证，我们证明了葡萄柚衍生的纳米囊泡（GDN）被肠道巨噬细胞选择性摄取，并改善葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎。这些作用是通过上调血红素加氧酶-1（HO-1）的表达和抑制肠道巨噬细胞中 IL-1β和 TNF-α的产生来介导的。GDN 具有固有生物相容性和生物降解性、在宽 pH 值范围内的稳定性以及对肠道巨噬细胞的靶向性，这促使我们进一步开发了一种新型基于 GDN 的口服递送系统。将抗炎药物甲氨蝶呤（MTX）纳入 GDN 中，并将 MTX-GDN 递送至小鼠体内，与游离 MTX 相比，显著降低了 MTX 的毒性，并且显著提高了其在 DSS 诱导的小鼠结肠炎中的治疗效果。这些发现表明，GDN 可作为肠道中的免疫调节剂，维持肠道巨噬细胞的稳态，并可开发用于小分子药物的口服递送，以减轻人类疾病中的炎症反应。
