Formulation of glycerolipidic prodrugs into PEGylated liposomes for brain delivery

Although numerous drugs are used to treat HIV infection with increasing efficacy, the patient’s brain is often infected by the virus and acts as a sanctuary where drugs cannot penetrate due to their low passage through the blood brain barrier. Therefore, the design of new medicine able to reach the brain is extremely challenging. An approach based on prodrug synthesis and encapsulation into PEGylated nanocarriers was proposed and applied to didanosine, a nucleosidic analogue used to treat HIV-1 associated dementia. In this study, appropriate formulations of PEGylated liposomes were designed to incorporate two glycerolipidic prodrugs of didanosine. Preparation methods based on Bangham’s or emulsion/evaporation techniques were optimized for each prodrug formulation according to the influence of critical parameters on vesicle size distribution. The obtained formulations exhibited particle size under 300 nm with high incorporation of prodrugs as shown by light scattering, optical microscopy experiments and differential scanning calorimetry. Finally the uptake of fluorescently labeled PEGylated formulations by rat brain immortalized endothelial cells modeling the BBB was evidenced by confocal laser scanning microscopy. All the results suggest that the encapsulation of didanosine prodrugs into PEGylated liposomes is a promising approach in the goal of increasing didanosine concentration in the brain and treating HIV-1-associated dementia.