Self-assembled polydopamine nanoparticles improve treatment in Parkinson's disease model mice and suppress dopamine-induced dyskinesia

Abstract

Although Levodopa (l-DOPA), a dopamine precursor, exhibits a high risk of dyskinesia, it remains the primary treatment in Parkinson's disease (PD), a progressive neurodegenerative disorder. In this study, we designed poly(l-DOPA)-based self-assembled nanodrug (Nano^DOPA) from amphiphilic block copolymer possessing poly(l-DOPA(OAc)₂), which is a precursor of l-DOPA as a hydrophobic segment, for treatment in a PD model mouse. Under physiological enzyme treatment, the poly(l-DOPA(OAc)₂) in the block copolymer was hydrolyzed to liberate l-DOPA gradually. Using the MPTP-induced PD mouse model, we observed that mice treated with Nano^DOPA demonstrated a significant improvement of PD symptoms compared to the l-DOPA treatment. Interestingly, the Nano^DOPA treatment did not cause the dyskinesia symptoms, which was clearly observed in the l-DOPA-treated mice. Furthermore, Nano^DOPA exhibited remarkably lower toxicity in vitro compared to l-DOPA, in addition with no noticeable Nano^DOPA toxicity observed in the treated mice. These results suggested that self-assembled Nano^DOPA is a promising therapeutic in the treatment of PD. STATEMENT OF SIGNIFICANCE: In this study, we proposed a therapeutic approach for the effective treatment of Parkinson's disease (PD) using newly designed poly(l-DOPA)-based self-assembled nanodrug (Nano^DOPA) prepared from amphiphilic block copolymers possessing poly(l-DOPA(OAc)₂), which is a precursor of l-DOPA as a hydrophobic segment, for treatment in a PD model mouse. Under physiological enzyme treatments, Nano^DOPA was hydrolyzed to liberate l-DOPA gradually, improving the pharmacokinetic value of l-DOPA. The mice treated with Nano^DOPA significantly improved PD symptoms compared to the l-DOPA treatment in a neurotoxin-induced PD mouse model. Interestingly, Nano^DOPA treatment did not cause dyskinesia symptoms, which was observed in the l-DOPA-treated mice. The obtained results in this study suggested that self-assembled Nano^DOPA is a promising therapeutic in the treatment of PD.

Keywords: BBB; Dopamine delivery; Parkinson's disease; Poly(l-DOPA); Polymer micelle-prodrug; Self-assembled drug.