title: N,N-Dimethyl Tertiary Amino Group Mediated Dual Pancreas- and Lung-Targeting Therapy against Acute Pancreatitis.
abstract: 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 in 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.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China.
authors.forename: Shi
authors.initials: S
authors.lastname: Luo
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China.
authors.forename: Peiwen
authors.initials: P
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China.
authors.forename: Zhengwu
authors.initials: Z
authors.lastname: Du
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Hu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China.
authors.forename: Zhirong
authors.identifier: 0000-0001-9118-5394
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000627:therapeutic use*; D002460:Cell Line; D056945:Hep G2 Cells; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008297:Male; D010179:Pancreas / Q000378:metabolism*; D010195:Pancreatitis / Q000188:drug therapy* / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry; D013656:Taurocholic Acid / Q000737:chemistry / Q000627:therapeutic use; D014315:Triterpenes / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D013656:Taurocholic Acid; C050414:celastrol
keywords: acute pancreatitis; anti-inflammatory; celastrol; dual-specific targeting; tertiary amine