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

Lars Linderoth, Peter Fristrup, Martin Hansen, Fredrik Melander, Robert Madsen, Thomas Lars Andresen, Günther H.J. Peters

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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 drug delivery system based on the triggered release of therapeutics from sPLA2-sensitive liposomes constituted of pro anticancer ether lipids, which become cytotoxic upon sPLA2-catalyzed hydrolysis has previously been established. To optimize the hydrolysis rate of the lipids and thereby optimizing the release profile of the drugs from the liposomes, we have synthesized a thio-ester pro anticancer ether lipid. Liposomes constituted of this lipid showed an altered rate of hydrolysis by sPLA2. We have tested the cytotoxicity of the thio-ester pro anticancer ether lipids toward cancer cells, and the results showed that the cytotoxicity is indeed maintained upon sPLA2 exposure. To further understand the origin for the observed different hydrolysis rates for the esters, we have applied molecular dynamics simulations and density functional theory. The combination of these theoretical methods has given valuable insight into the molecular mechanism for sPLA2 action on sulfur-containing phospholipids. It appears that the enzyme-catalyzed hydrolysis of thio-esters follow a different pathway compared to the hydrolysis pathway of the free thio-ester.
Original languageEnglish
JournalJournal of the American Chemical Society
Volume131
Issue number34
Pages (from-to)12193-12200
Number of pages8
ISSN0002-7863
DOIs
Publication statusPublished - 2009

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