Novel phospholipid (PL)‐cyclosporine conjugates were prepared and studied as potential prodrugs for inflammatory bowel disease (IBD). Our approach relies on phospholipase A₂ (PLA₂), which is overexpressed in the inflamed intestinal tissues, as the prodrug activator to potentially release cyclosporine at the site of inflammation. PL‐cyclosporine prodrug conjugates with methylene linkers of various lengths between the sn‐2 position of the PL and cyclosporine were synthesized and evaluated for in vitro activation. Surprisingly, despite previous work indicating that conjugates with six methylene linkers between the lipid and drug would suffer rapid enzymatic hydrolysis, with cyclosporine this was not observed. However, compounds with longer linkers (n=10, 12 methylene units) display complete release of the drug by PLA₂‐catalyzed hydrolysis, thus demonstrating the importance and profound impact of structural fine‐tuning. This study represents a proof‐of‐concept for our hypothesis and a first step towards a truly targeted IBD treatment with cyclosporine that could be administered throughout the GI tract.

中文翻译：

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针对炎症性肠病（IBD）治疗的磷脂酰环孢素前药：设计，合成和体外验证。

制备了新型磷脂（PL）-环孢菌素偶联物，并将其作为炎症性肠病（IBD）的潜在前药进行了研究。我们的方法依赖于在发炎的肠组织中过表达的磷脂酶A ₂（PLA ₂）作为前药激活剂，可在炎症部位释放环孢菌素。合成了PL-环孢素前药与在PL和环孢素的sn-2位置之间具有不同长度的亚甲基接头的缀合物，并进行了体外活化评估。出人意料的是，尽管先前的工作表明在脂质和药物之间具有六个亚甲基接头的缀合物将遭受快速酶水解，但对于环孢菌素却没有观察到。但是，具有较长连接子的化合物（n= 10，12个亚甲基单元）通过PLA ₂催化水解显示药物已完全释放，因此证明了结构微调的重要性和深远影响。这项研究代表了我们假说的概念验证，也是朝着可以在整个胃肠道内施用的环孢素进行真正针对性IBD治疗的第一步。