Novel nanostructured lipid carriers based on Ω-3 polyunsaturated fatty acids and TAT peptide for neurodegenerative disease treatment

Résumé

Neurodegenerative diseases (NDs) are an accelerating global problem, but we still lack routes to develop effective therapeutics. In this quest, it is crucial to identify novel drug candidates or drug carriers, which cross the blood-brain barrier (BBB) and reach the brain tissue. In the present doctoral thesis, we have focused on nanostructured lipid carriers (NLCs) development for the targeted delivery of NTFs. The NLCs surface modification with chitosan (CS) and TAT effectively deliver glial derived neurotrophic factor (GDNF) NTF in Parkinson Disease (PD) animal model, restoring its motor activity and modulation of the reactive gliosis. Moreover, the chronic administration of ¿-3 fatty acids to PD animal model led to animals¿ dopaminergic system improvement, and modulate the present neuroinflammation and oxidative stress. As a following step, the tested functional lipids were used to NLC development, retaining their ability as neuroprotective and anti-inflammatory agents. Finally, the compose NLCs with ¿-3 functional lipids and surface modified with TAT and CS tested positive to pass across human BBB in vitro model, showing as a good candidate to target the brain. The anti-inflammatory and anti-oxidative potential of these ¿-3 nanocarriers successfully counteracted the inflammatory state present in human microglia cell line. The co administration with glial derived neurotrophic factor (GDNF) triggered the endogenous anti-oxidative system present in microglia. All these data support the development of NLC composed of functional lipids, and surface modified with different moieties, to target and treat CNS related disorders.