Mechanistic Study of the sPLA2-Mediated Hydrolysis of a Thio-ester Pro Anticancer Ether Lipid

• DOI: 10.1021/ja901412j
• Publication Date: 2009-08-07T14:24:31Z
• Authors: Lars Linderoth; Peter Fristrup; Martin Hansen; Fredrik Melander; Robert Madsen; Thomas L. Andresen; Günther H. Peters
• Keywords: Thio-

Secretory phospholipase A2 (sPLA2) is an interesting enzyme for triggered liposomal drug delivery to tumor tissue due the overexpression of sPLA2 in cancerous tissue. A system based on release therapeutics from sPLA2-sensitive liposomes constituted pro anticancer ether lipids, which become cytotoxic upon sPLA2-catalyzed hydrolysis has previously been established. To optimize rate lipids and thereby optimizing profile drugs liposomes, we have synthesized a thio-ester lipid. Liposomes this lipid showed altered by sPLA2. We tested cytotoxicity toward cancer cells, results that indeed maintained exposure. further understand origin observed different rates esters, applied molecular dynamics simulations density functional theory. The combination these theoretical methods given valuable insight into mechanism action sulfur-containing phospholipids. It appears enzyme-catalyzed thio-esters follow pathway compared free thio-ester.