College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.
College of Chemical Engineering, Sichuan University, Chengdu, 610065, China.
J Control Release. 2019 Dec 28;316:66-78. doi: 10.1016/j.jconrel.2019.10.054. Epub 2019 Nov 1.
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 π-π stacking interactions of ATK, prodrug B-ATK-T could self-assemble into nanoparticles (NP) in water containing lecithin and DSPE-PEG. The morphology of B-ATK-T NP (approximate 100-120nm) 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.
一种自组装和氧化降解的 Janus 前药，称为 Bud-ATK-Tem（B-ATK-T），由 ROS 响应性芳构化硫缩酮（ATK）连接抗炎药物布地奈德（Bud）和抗氧化剂 Tempo（Tem）组成。得益于 ATK 的疏水相互作用和π-π堆积相互作用，前药 B-ATK-T 可以在含有卵磷脂和 DSPE-PEG 的水中自组装成纳米颗粒（NP）。透射电子显微镜证实，B-ATK-T NP 的形态为规则的球形（约 100-120nm）。B-ATK-T NP 具有较高的载药量，Bud 的载药量为 41.23%，Tem 的载药量为 15.55%。B-ATK-T NP 中的药物快速释放是一种广泛的依赖活性氧（ROS）的方式。在模仿炎症的微环境或佛波醇 12-肉豆蔻酸 13-乙酸酯（PMA）刺激的巨噬细胞中，B-ATK-T NP 中的 Bud 和 Tem 可以在短时间内释放超过 98%。药物的同时和比例释放确保了 B-ATK-T NP 可以提高抗炎和抗氧化的联合疗效。值得注意的是，B-ATK-T NP 可以通过口服途径被动积累，并在患有炎症性肠病（IBD）的小鼠的炎症结肠中显著增加最大药物浓度，从而避免潜在的全身副作用。B-ATK-T NP 不仅可以通过抑制氧化和促炎介质的表达来缓解结肠炎，而且可以显著降低结肠炎引起的死亡率。总之，自组装的 Janus 前药 B-ATK-T NP 是治疗 IBD 的一种很有前途的候选疗法，甚至对其他炎症性疾病也是如此。
