Linderoth, Lars and Fristrup, Peter and Hansen, Martin and Melander, Fredrik and Madsen, Robert and Andresen, Thomas L. and Peters, Günther H. (2009) Mechanistic Study of the sPLA_2-Mediated Hydrolysis of a Thio-ester Pro Anticancer Ether Lipid. Journal of the American Chemical Society, 131 (34). pp. 12193-12200. ISSN 0002-7863 http://resolver.caltech.edu/CaltechAUTHORS:20090911-153601564
- Published Version
See Usage Policy.
- Supplemental Material
See Usage Policy.
Use this Persistent URL to link to this item: http://resolver.caltech.edu/CaltechAUTHORS:20090911-153601564
Secretory phospholipase A_2 (sPLA_2) is an interesting enzyme for triggered liposomal drug delivery to tumor tissue due the overexpression of sPLA_2 in cancerous tissue. A drug delivery system based on the triggered release of therapeutics from sPLA_2-sensitive liposomes constituted of pro anticancer ether lipids, which become cytotoxic upon sPLA_2-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 sPLA_2. 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 sPLA_2 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 sPLA_2 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.
|Additional Information:||Copyright © 2009 American Chemical Society. Received February 23, 2009; Publication Date (Web): August 7, 2009. G.H.P. acknowledges financial support from the Danish National Research Foundation via a grant to MEMPHYS - Center for Biomembrane Physics. Simulations were performed at the Danish Center for Scientific Computing at the University of Southern Denmark. L.L. is supported via a scholarship from the Technical University of Denmark. P.F. acknowledges financial support from the Carlsberg foundation, Lundbeck foundation and The Danish Council for Independent Research | Technology and Production Sciences. Supporting Information: Detailed experimental procedures for organic synthesis of the lipids studied (including ^1H and ^(13)C NMR spectral data), preparation of liposomes, differential scanning calorimetry (DSC), activity measurements, and cytotoxicity assays; description of the computational methods applied to perform molecular dynamics simulations; mean distances and their standard deviations between selected atoms extracted from the simulations (Table S1); description of the computational method used for the DFT calculations (including Figures S1 and S2, XYZ coordinates, and solution-phase energies). This material is available free of charge via the Internet at http://pubs.acs.org.|
|Official Citation:||Mechanistic Study of the sPLA2-Mediated Hydrolysis of a Thio-ester Pro Anticancer Ether Lipid Lars Linderoth, Peter Fristrup, Martin Hansen, Fredrik Melander, Robert Madsen, Thomas L. Andresen, Gnther H. Peters Journal of the American Chemical Society 2009 131 (34), 12193-12200|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||George Porter|
|Deposited On:||07 Oct 2009 21:36|
|Last Modified:||26 Dec 2012 11:22|
Repository Staff Only: item control page