Synthesis of Metal Complex Modified Phospholipids by Phospholipase D-Catalyzed Transphosphatidylation

Abstract

The synthesis of ferrocenyl-functionalized phospholipid was achieved through a biphasic transphosphatidylation reaction catalyzed by phospholipase D. Thus, the 1,2-distearoyl-sn-glycero-3-phosphocholine headgroup was modified with hydroxymethylferrocene. 1,2-distearoyl-sn-glycero-3-phosphocholine was chosen because it bears a choline group required for successful phospholipase D-catalysis. The use of hydroxymethylferrocene, as an electroactive tether, was appropriate since the present transphosphatidylation reaction is specific to primary alcohols. Mass spectrometry and phosphorus nuclear magnetic resonance analysis confirmed the formation of the redox active phospholipid and also revealed downstream instabilities that will need to be resolved prior to use in liposome assemblies.

Synthesis of Redox Active Ferrocene-Modified Phospholipids by Transphosphatidylation Reaction and Chronoamperometry Study of the Corresponding Redox Sensitive Liposome

“…The only available reported study suffered from severe redox phospholipid instability that prevented the formation of organometallic redox active liposomes. 18 Specifically, the synthesis of a redox active 1,2distearoyl-sn-glycero-3-phosphocholine (DSPC) bearing a ferrocenemethanol function, DSP-OCH 2 Fc, resulted in the formation of an unstable product because the redox headgroup underwent hydrolysis and/or S N 2 reactions, which favored the formation of phosphatidic acid. To overcome this limitation, it was hypothesized that increasing the length of the alkyl chain between the phosphorus and the ferrocene group should further stabilize the redox active phospholipid product.…”

“…Importantly, liposome surface functionalization with organometallic pendents remains unexplored. The only available reported study suffered from severe redox phospholipid instability that prevented the formation of organometallic redox active liposomes . Specifically, the synthesis of a redox active 1,2-distearoyl- sn -glycero-3-phosphocholine (DSPC) bearing a ferrocenemethanol function, DSP-OCH 2 Fc, resulted in the formation of an unstable product because the redox headgroup underwent hydrolysis and/or S N 2 reactions, which favored the formation of phosphatidic acid.…”

Asymmetric cationic liposomes designed for heat-activated association with cells

“…More advanced systems exhibit a stimulus-responsive property in response to, e.g., temperature, 6 enzymes, 7 or redox reactions. 8 Responsive systems provide the possibility to preserve the function of enhanced uptake during circulation and to activate it at the targeted sites by the application of stimulus. Additionally, temperature-responsive liposomes offer the possibility of releasing drugs in response to hyperthermia treatments.…”