This thesis investigates a number of issues related to synthesis and functionalization of liposomes with possible future drug delivery applications in mind.
Despite advances in cancer treatment, side effects caused by the high toxicity of anti-cancer drugs towards healthy cells continue to be a major problem. A strategy to overcome this problem is the use of liposomes as drug delivery systems. Liposomes can be designed for specific purposes by altering their biophysical properties. Ideally, liposomes can encapsulate the active drug and only release it once the tumor has been reached. In practice this has not yet been achieved. This thesis investigates a number of issues related to synthesis of liposomes with possible future drug delivery applications in mind.
Firstly, a series of phospholipids were synthesized in order to perform a structure- activity relationship study of an enzyme, secretory phospholipase A2 (sPLA2) capable of hydrolyzing phospholipids in the sn-2 position specifically. This enzyme is over-expressed in several types of cancer and is under evaluation as a potential trigger for drug release from a new generation of liposomal drug delivery systems. Based on previous observations and MD experiments, we developed a theory to predict and explain the activity of the enzyme in engineered phospholipids. According to our theory, two aspects of the enzyme-substrate interactions are primordial for an effective hydrolysis to occur: the formation of a constructive Michaelis-Menten complex, and access of water to the hydrolysis site. The theory was confirmed by experiments.
Secondly, surface functionalization of liposomes was studied. The copper mediated [3+2] azide-alkyne cycloaddition has been successfully applied for this purpose by different groups, but no general optimization has been developed for the reaction on functionalized liposomes. Our results indicate that the reaction is most efficient when the liposome carries the alkyne functionality rather than the azide. We also investigated and developed a novel selective method for functionalizing liposomes, which has not yet been reported in the literature, based on the reaction between propargyl-amine decorated liposomes and isothiocyanate derived coupling partners that results in a coupling via formation of an iminothiazolidine.
Thirdly, the synthesis of sn-2 glyceryl 10,16-dihydroxyhexadecanoate is reported, in the context of the identification of the process of formation of the cutin polymer, one the primary reactive components of the epidermis of land plants.
Finally, a last section of the project differs greatly as it is not related to liposomes. Here, a C3 symmetric phosphine oxide was synthesized. We intend to test it, after reduction to the phosphin, as a ligand in organometallic catalyzed reactions. The ultimate goal is to obtain enantioselectivity, introduced by the organization of aryl substituents around phosphorous in our ligand.