Targeted Liposomal Co-Delivery Dopamine with 3-n-Butylphthalide for Effective Against Parkinson's Disease in Mice Model.

Introduction: Parkinson's disease (PD) is a multifactor-induced neurodegenerative disease with high incidence in the elderly population. We found for the first time that the combination of dopamine (DA) and 3-n-butylphthalide (NBP) has great potential for the synergistic treatment of PD. To further improve the therapeutic performance of the drugs, a brain-targeting liposomal co-delivery system encapsulating NBP and DA ((NBP+DA)-Lips-RVG29) was designed using a rabies virus polypeptide with 29 amino acids (RVG29) as the targeting ligand.

Methods: The synergistic neuroprotective effects of NBP and DA were assessed in 6-OHDA-induced PC12 cells. Then, (NBP+DA)-Lips-RVG29 loading with NBP and DA at an optimal ratio was prepared using the thin-film hydration and sonication method. The physicochemical and biological characterization of (NBP+DA)-Lips-RVG29 were systemically investigated, and the therapeutic efficiency and underlying mechanisms of (NBP+DA)-Lips-RVG29 were also explored in vitro and in vivo. Finally, the safety of (NBP+DA)-Lips-RVG29 was evaluated.

Results: The synergistic effects of NBP and DA peaked at 1:1 (NBP/DA, mol/mol). The functionalized liposomes showed significantly higher uptake efficiency and blood-brain barrier (BBB) penetration efficiency in vitro. After systemic administration, (NBP+DA)-Lips-RVG29 prolonged the blood circulation of drugs, enhanced BBB penetration and increased drug accumulation in the striatum, substantia nigra and hippocampus. Moreover, (NBP+DA)-Lips-RVG29 showed excellent neuroprotective effects in a cellular PD model of PC12 cells and improved therapeutic efficacy in a PD mouse model. Furthermore, the safety evaluation of (NBP+DA)-Lips-RVG29 revealed no systemic toxicity.

Conclusion: NBP and DA exhibited the synergistic anti-PD effects. The RVG29-modified liposomes encapsulating NBP and DA contributed to the accumulation of drugs in the brain lesions area of PD and further improved treatment efficacy. Therefore, (NBP+DA)-Lips-RVG29 represents a promising strategy for the treatment of PD and other neurodegenerative diseases.