Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China; Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Int J Pharm. 2021 Sep 5;606:120836. doi: 10.1016/j.ijpharm.2021.120836. Epub 2021 Jul 2.
The present study aimed at constructing an oral nanoparticle delivery system loaded with tacrolimus (FK506) for effective treatment of inflammatory bowel disease. A FK506/HP-β-CD inclusion compound was prepared by grinding to increase drug solubility. To address the side- effects in non-target organs and systemic toxicity of FK506, pH-responsive Eudragit S100 (ES100) and hyaluronic acid (HA) with high affinity to CD44 receptor were adsorbed onto the surface of chitosan (CS) nanoparticles loaded with FK506/HP-β-CD through electrostatic interactions to obtain FK506@ES100/HA/CS/HP-β-CD nanoparticles (FK506@EHCh NPs). Caco-2 cells and Raw 264.7 macrophages were used to confirm the lack of cytotoxicity and good uptake ability of the newly generated nanoparticles. FK506@EHCh NPs significantly suppressed secretion of TNF-α, IL-1β and IL-6 by LPS-activated Raw 264.7 macrophages. A dextran sodium sulfate (DSS)-induced inflammatory bowel disease (IBD) murine model was established to further confirm the colon targeting and in vivo efficacy of oral IR-775@EHCh NPs. Based on the collective results, we conclude that packaging FK506 into active targeting nanocarriers sensitive to pH facilitates concentration of the drug within the sites of intestinal inflammation and improves the drug levels in target tissues, thus avoiding systemic side-effects and improving efficacy. In view of the promising results obtained in this study, the potential of EHCh nanoparticles for drug delivery and targeted treatment of inflammatory bowel disease warrants further investigation.
本研究旨在构建一种载有他克莫司（FK506）的口服纳米颗粒递药系统，以有效治疗炎症性肠病。通过研磨制备 FK506/HP-β-CD 包合物以提高药物溶解度。为了解决 FK506 非靶器官的副作用和全身毒性问题，通过静电相互作用将对 pH 敏感的 Eudragit S100（ES100）和与 CD44 受体高度亲和的透明质酸（HA）吸附到载有 FK506/HP-β-CD 的壳聚糖（CS）纳米颗粒表面上，得到 FK506@ES100/HA/CS/HP-β-CD 纳米粒（FK506@EHCh NPs）。使用 Caco-2 细胞和 Raw 264.7 巨噬细胞证实新生成的纳米粒无细胞毒性且具有良好的摄取能力。FK506@EHCh NPs 显著抑制 LPS 激活的 Raw 264.7 巨噬细胞分泌 TNF-α、IL-1β 和 IL-6。建立葡聚糖硫酸钠（DSS）诱导的炎症性肠病（IBD）小鼠模型，进一步证实口服 IR-775@EHCh NPs 的结肠靶向性和体内疗效。基于综合结果，我们得出结论，将 FK506 包装到对 pH 敏感的主动靶向纳米载体中有助于将药物集中在肠道炎症部位，并提高靶组织中的药物水平，从而避免全身副作用并提高疗效。鉴于本研究中取得的有前景的结果，EHCh 纳米粒在药物传递和炎症性肠病的靶向治疗方面具有很大的潜力，值得进一步研究。
