Mechanistic Study of the sPLA-Mediated Hydrolysis of a Thio-ester Pro Anticancer Ether Lipid.
Secretory phospholipase A (sPLA) is an interesting enzyme for triggered liposomal drug delivery to tumor tissue due the overexpression of sPLA in cancerous tissue. A drug delivery system based on the triggered release of therapeutics from sPLA-sensitive liposomes constituted of pro anticancer ether...
| Publicado en: | Journal of the American Chemical Society Vol. 131; no. 34; pp. 12193 - 12201 |
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| Autores principales: | , , , , , , |
| Formato: | Artículo |
| Publicado: |
American Chemical Society
9/2/2009
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| Materias: | |
| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=hlh&AN=44230192&site=ehost-live header: @attributes: shortDbName: hlh uiTerm: 44230192 longDbName: Humanities International Complete uiTag: AN controlInfo: bkinfo: jinfo: jid: 00027863 ACS jtl: Journal of the American Chemical Society issn: 00027863 maglogo: N pubinfo: dt: 9/2/2009 vid: 131 iid: 34 pid: 997 pub: American Chemical Society artinfo: ui: 44230192 10.1021/ja901412j ppf: 12193 ppct: 8 formats: tig: atl: Mechanistic Study of the sPLA-Mediated Hydrolysis of a Thio-ester Pro Anticancer Ether Lipid. aug: au: Linderoth, Lars Fristrup, Peter Hansen, Martin Melander, Fredrik Madsen, Robert Andresen, Thomas L. Peters, Günther H. affil: Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark Novo Nordisk A/S, Protein and Peptide Chemistry 3, Novo Nordisk Park, DK-2760 Måløv, 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 DTU Nanotech, Technical University of Denmark, DK-4000 Roskilde, Denmark Department of Chemistry, MEMPHYS-Center for Biomembrane Physics, Technical University of Denmark, DK-2800 Kgs. Lyngby Denmark su: Density functionals Hydrolysis Phospholipids Liposomes Cytoplasm Ethers sug: subj: Density functionals Hydrolysis Phospholipids Liposomes Cytoplasm Ethers ab: Secretory phospholipase A (sPLA) is an interesting enzyme for triggered liposomal drug delivery to tumor tissue due the overexpression of sPLA in cancerous tissue. A drug delivery system based on the triggered release of therapeutics from sPLA-sensitive liposomes constituted of pro anticancer ether lipids, which become cytotoxic upon sPLA-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. 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 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 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. pubtype: Academic Journal doctype: Article src: R language: English refInfo: copyright: @attributes: flag: Y dt: @attributes: year: 2009 holdings: @attributes: islocal: N |
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