Abstract

Inflammatory bowel disease (IBD) is one of the most common intestinal disorders, with increasing global incidence and prevalence. Numerous therapeutic drugs are available but require intravenous administration and are associated with high toxicity and insufficient patient compliance. Here, an oral liposome that entraps the activatable corticosteroid anti-inflammatory budesonide was developed for efficacious and safe IBD therapy. The prodrug was produced via the ligation of budesonide with linoleic acid linked by a hydrolytic ester bond, which was further constrained into lipid constituents to form colloidal stable nanoliposomes (termed budsomes). Chemical modification with linoleic acid augmented the compatibility and miscibility of the resulting prodrug in lipid bilayers to provide protection from the harsh environment of the gastrointestinal tract, while liposomal nanoformulation enables preferential accumulation to inflamed vasculature. Hence, when delivered orally, budsomes exhibited high stability with low drug release in the stomach in the presence of ultra-acidic pH but released active budesonide after accumulation in inflamed intestinal tissues. Notably, oral administration of budsomes demonstrated favorable anti-colitis effect with only ∼7% mouse body weight loss, whereas at least ∼16% weight loss was observed in other treatment groups. Overall, budsomes exhibited higher therapeutic efficiency than free budesonide treatment and potently induced remission of acute colitis without any adverse side effects. These data suggest a new and reliable approach for improving the efficacy of budesonide. Our in vivo preclinical data demonstrate the safety and increased efficacy of the budsome platform for IBD treatment, further supporting clinical evaluation of this orally efficacious budesonide therapeutic.

摘要

炎症性肠病 (IBD) 是最常见的肠道疾病之一，其全球发病率和患病率不断增加。许多治疗药物是可用的，但需要静脉内给药，并且与高毒性和患者依从性不足有关。在这里，开发了一种包埋可激活皮质类固醇抗炎布地奈德的口服脂质体，用于有效和安全的 IBD 治疗。前药是通过布地奈德与通过水解酯键连接的亚油酸连接产生的，亚油酸被进一步限制为脂质成分，形成胶体稳定的纳米脂质体（称为芽体）。用亚油酸进行化学修饰增强了所得前药在脂质双层中的相容性和混溶性，以提供免受胃肠道恶劣环境影响的保护，而脂质体纳米制剂能够优先积累到发炎的脉管系统。因此，当口服递送时，芽体在超酸性 pH 存在下表现出高稳定性和低药物释放，但在发炎的肠组织中积累后释放活性布地奈德。值得注意的是，口服给予芽体显示出良好的抗结肠炎作用，小鼠体重仅减轻约 7%，而在其他治疗组中观察到至少约 16% 的体重减轻。全面的，与游离布地奈德治疗相比，芽体表现出更高的治疗效率，并且有效地诱导急性结肠炎缓解而没有任何不良副作用。这些数据提示了一种新的可靠方法来提高布地奈德的疗效。我们的体内临床前数据证明了用于 IBD 治疗的 budsome 平台的安全性和更高的疗效，进一步支持了这种口服有效的布地奈德治疗的临床评估。