Journal article
Mechanistic Study of the sPLA2-Mediated Hydrolysis of a Thio-ester Pro Anticancer Ether Lipid
Department of Chemistry, MEMPHYS-Center for Biomembrane Physics, Technical University of Denmark, DK-2800 Kgs. Lyngby Denmark, Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark, Materials and Process Simulation Center (139-74), California Institute of Technology, Pasadena, California 91125, LiPlasome Pharma A/S, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark, and DTU Nanotech, Technical University of Denmark, DK-4000 Roskilde, Denmark
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.
Language: | English |
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Publisher: | American Chemical Society |
Year: | 2009 |
Pages: | 12193-12200 |
ISSN: | 15205126 and 00027863 |
Types: | Journal article |
DOI: | 10.1021/ja901412j |