Multiple Protective Roles of Nanoliposome‐Incorporated Baicalein against Alpha‐Synuclein Aggregates

Nanoparticles are useful for increasing drug stability, solubility, and availability. The small molecule baicalein inhibits fibrillation, and detoxifies aggregates of α‐synuclein (αSN) associated with Parkinson's disease (PD), but it suffers from instability, low solubility and consequent low availability. Here it is demonstrated that incorporation of baicalein into zwitterionic nanoliposomes (NLP‐Ba) addresses these problems. NLP‐Ba inhibits αSN fibril initiation, elongation, secondary nucleation, and also depolymerizes mature fibrils more effectively than free baicalein and prevents soluble αSN aggregates from seeding new fibrils. Importantly, NLP‐Ba perturbs oligomers’ capacity to permeabilize the membrane. The interaction between NLP‐Ba and αSN is confirmed by different biophysical techniques. This nanosystem crosses the blood‐brain barrier in vitro and is effective against rotenone neurotoxicity in vivo. The effect of NLP‐Ba on αSN fibrillation/cytotoxicity is attributed to a combination of free baicalein and empty NLPs. The results indicate a neuroprotective role for NLP‐Ba in decreasing αSN pathogenicity in PD and highlight the use of nanoliposomes to mobilize poorly soluble hydrophobic drugs. The flavonoid baicalein inhibits aggregation of proteins involved in neurodegenerative diseases but its use is limited by low solubility and chemical instability. By incorporating baicalein into zwitterionic PEG‐covered nanoliposomes, stability and solubility are greatly improved while functionality is retained. Baicalein‐loaded nanoliposomes cross the blood‐brain barrier and suppress Parkinson's Disease in an animal model. Thus, nanoliposomes mobilize hydrophobic drugs very well.