| 19663381 |
Linderoth L, Fristrup P, Hansen M, Melander F, Madsen R, Andresen TL, Peters GH: Mechanistic study of the sPLA2-mediated hydrolysis of a thio-ester pro anticancer ether lipid. J Am Chem Soc. 2009 Sep 2;131(34):12193-200.
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. |
36(0,1,1,6) |