Premium
Phospholipid Cyclosporine Prodrugs Targeted at Inflammatory Bowel Disease (IBD) Treatment: Design, Synthesis, and in Vitro Validation
Author(s) -
Manda Jagadeesh Nagendra,
Markovic Milica,
Zimmermann Ellen M.,
BenShabat Shimon,
Dahan Arik,
Aponick Aaron
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000317
Subject(s) - prodrug , pharmacology , in vitro , chemistry , drug , inflammatory bowel disease , phospholipid , conjugate , medicine , biochemistry , disease , membrane , mathematical analysis , mathematics
Novel phospholipid (PL)‐cyclosporine conjugates were prepared and studied as potential prodrugs for inflammatory bowel disease (IBD). Our approach relies on phospholipase A 2 (PLA 2 ), 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 PLA 2 ‐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.