期刊
MOLECULAR PHARMACEUTICS
卷 14, 期 5, 页码 1771-1781出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.7b00028
关键词
tertiary amine; dual-specific targeting; acute pancreatitis; celastrol; anti-inflammatory
资金
- National Science Foundation of China [81473169]
Acute pancreatitis (AP) is a sudden inflammation of the pancreas with-high mortality rate worldwide. As a severe complication to AP; acute lung injury has been the major cause of death among patients with AP. Poor penetration across the blood pancreas barrier (BPB) and insufficient drug accumulation at the target site often result in poor therapeutic outcome. Our previous work successfully demonstrated a dual-specific targeting strategy to pancreas and lung using a phenolic propanediamine moiety. Inspired by this, a simplified ligand structure, N,N-dimethyl tertiary amino group, was covalently conjugated to celastrol (CLT) to afford:tertiary amino conjugates via either an ester (CP), or an amide linkage (CTA). With sufficient plasma stability, CTA was subjected to-the following studies. Compared to CLT, CTA exhibited excellent cellular uptake efficiency in both rat pancreatic acinar cell line (AR42J) and human pulmonary alveolar epithelial cell line (A549).,Organic cation transporters were proven to be responsible for this, active transport process. Given systemically, CTA specifically distributed to pancreases. and lungs in rats thus resulting a 2.59-fold and 3.31-fold increase in-tissue-specific accumulation as compared to CLT. After CTA treatment, tissue lesions were greatly alleviated and the levels of proinflammatory cytokines were downregulated in rats with sodium taurocholate induced AP. Furthermore, CTA demonstrated marginal adverse effect against major organs with reduced cardiac toxicity compared to CLT. Together, tertiary amine mediated dual pancreas- and lung-targeting therapy represents an efficient and safe strategy for AP management.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据