Gallic acid loaded onto polyethylenimine-coated human serum albumin nanoparticles (PEI-HSA-GA NPs) stabilizes α-synuclein in the unfolded conformation and inhibits aggregation

The aggregation of the 140-residue protein α-synuclein (αSN) plays a major role in the pathogenesis of different neurodegenerative disorders such as Parkinson's Disease (PD). Previous reports indicated that the antioxidant gallic acid (GA) can inhibit αSN aggregation. As the transport of GA to the brain due to the lipophilic nature of endothelial cells is prevented, we loaded GA onto positively charged polyethylenimine-coated human serum albumin (PEI-HSA) NPs and investigated the properties of these nanoparticles as drug carriers. Using an array of different techniques, we determined that GA on GA loaded PEI-HSA NPs (PEI-HSA-GA NPs) decreases the interaction of the NPs with αSN and stabilizes αSN in the unfolded conformation. These interactions lead to different effects on the αSN aggregation. While the rate of αSN aggregation increased in the presence of PEI-HSA NPs and free GA (PEI-HSA NPs + GA) due to the effect of PEI-HSA NPs, PEI-HSA-GA NPs inhibited αSN aggregation to the same extent as free GA in a concentration dependent manner. Additionally, GA inhibited the interaction of PEI-HSA-GA NPs with calcein filled vesicles, in accordance with our previous study indicating that loading GA can decrease the toxicity of PEI-HSA NPs. Also, PEI-HSA NPs not only inhibited αSN oligomers' perturbation of the membrane but also decreased the level of toxic oligomers. We conclude from our data that PEI-HSA-GA NPs are promising candidates for efficient delivery of GA to the brain.