A self-assembled, ROS-responsive Janus-prodrug for targeted therapy of inflammatory bowel disease
A self-assembled, ROS-responsive Janus-prodrug for targeted therapy of inflammatory bowel disease
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DOI：
10.1016/j.jconrel.2019.10.054
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发表时间：
2019-12-28
影响因子：
10.8
通讯作者：
Zhang, Qixiong
中科院分区：
文献类型：
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作者：
Li, Shanshan;Xie, Aiqing;Zhang, Qixiong
由ROS敏感的芳香化硫缩酮（ATK）连接抗炎药布地奈德（Bud）和抗氧化剂tempol（Tem），合成了一种自组装的氧化降解Janus前药，命名为Bud-ATK-Tem（B-ATK-T）。利用ATK的疏水相互作用和Tc-Tc堆积作用，前药B-ATK-T可以在卵磷脂和DSPE-PEG（2K）的水溶液中自组装成纳米粒（NP）。通过透射电子显微镜证实B-ATK-T NP的形态（约100-120 nm）为规则的球形。B-ATK-T纳米粒具有较高的载药量，其中Bud的载药量为41.23%，Tem的载药量为15.55%。药物从B-ATK-T NP的快速释放以广泛的活性氧（ROS）依赖性方式进行。B-ATK-T NP中超过98%的Bud和Tem可以在模拟炎症微环境或佛波醇-12-肉豆蔻酸-13-醋酸酯（PMA）刺激的巨噬细胞中短时间内释放。药物以同时和成比例的方式释放，确保B-ATK-T NP可以增加抗炎和抗氧化的联合功效。值得注意的是，B-ATK-T NP通过口服途径可以被动积累并显著增加炎症性肠病（IBD）小鼠炎症结肠中的最大药物浓度，并且避免潜在的全身副作用。B-ATK-T NP不仅能通过抑制氧化和促炎介质的表达来缓解结肠炎，而且能显著降低结肠炎引起的死亡。综上所述，自组装的Janus前药B-ATK-T NP是IBD甚至其他炎症性疾病的有希望的候选疗法。
A self-assembled and oxidation-degradable Janus-prodrug, termed as Bud-ATK-Tem (B-ATK-T), was fabricated by ROS-responsive aromatized thioketal (ATK) linked anti-inflammatory drug budesonide (Bud) and antioxidant tempol (Tem). Benefiting from the hydrophobic interactions and Tc-Tc stacking interactions of ATK, prodrug B-ATK-T could self-assemble into nanoparticles (NP) in water containing lecithin and DSPE-PEG(2K). The morphology of B-ATK-T NP (approximate 100-120 nm) was confirmed to be regular spherical by transmission electron microscope. B-ATK-T NP was endowed high drug loading content with 41.23% for Bud and 15.55% for Tem. The rapid drug release from B-ATK-T NP proceeded in an extensive reactive oxygen species (ROS)-dependent manner. More than 98% of Bud and Tem in B-ATK-T NP could release in the mimic inflammation microenvironment or phorbol-12-myristate-13-acetate (PMA)-stimulated macrophages within short time. The release of drugs in a simultaneous and proportional manner ensures that B-ATK-T NP can increase the combined efficacy of anti-inflammation and anti-oxidation. It is worth noting that B-ATK-T NP could be passively accumulated and dramatically increasing the maximum drugs concentration in the inflamed colon of mice with inflammatory bowel disease (IBD) by oral route, and avoiding potential systemic side effects. B-ATK-T NP could not only relieve colitis via inhibiting the expression of oxidative and proinflammatory mediators more than combination of free drugs, but also significantly reduce colitis-caused death. Taken together, the self-assembled, Janus-prodrug B-ATK-T NP is a promising candidate therapies for IBD, even for other inflammatory diseases.