Structural characterisation of nucleoside loaded low density lipoprotein as a main criterion for the applicability as...

The potential role of human low density lipoprotein (LDL) particles as delivery system for lipophilic, cytotoxic drugs critically depends on their structural integrity. In the present study, LDL particles were loaded with antineoplastic prodrugs, i.e. monooleoyl (MOT)- and dioleoyl (DOT)- thymidine esters by different techniques. Using the reconstitution method MOT shows the highest incorporation efficiency with over 80% of the initial drug associated with LDL. In contrast, for the more lipophilic DOT the incorporation efficiency for reconstitution, dry film as well as dimethylsulfoxide method was extremely low. Structural changes upon drug loading were monitored by differential scanning calorimetry (DSC) and small angle X-ray scattering (SAXS). The results show that the influence of MOT and DOT is predominantly confined to the surface monolayer of LDL seen as a destabilisation of the protein moiety and a small increase in particle diameter. The core lipid region of the LDL-drug complexes remains essentially unaffected, as verified by undisturbed core lipid arrangement and core lipid melting behaviour.