A brain targeting functionalized liposomes of the dopamine derivative N-3,4-bis(pivaloyloxy)-dopamine for treatment of Parkinson's disease

• Published in: Journal of controlled release Vol. 277; pp. 173 - 182
• Main Authors: Qu, Mengke, Lin, Qing, He, Shanshan, Wang, Luyao, Fu, Yao, Zhang, Zhirong, Zhang, Ling
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.05.2018
• Subjects: Amino Acid Sequence; Animals; Brain - diagnostic imaging; Brain - drug effects; Brain - metabolism; Brain targeting; Cell Line, Tumor; Dopamine - administration & dosage; Dopamine - analogs & derivatives; Dopamine - metabolism; Drug Delivery Systems - methods; Glycoproteins - administration & dosage; Glycoproteins - metabolism; HeLa Cells; Humans; Liposomes; Male; Mice; Mice, Nude; N-3,4-bis(pivaloyloxy)-dopamine; Parkinson Disease - diagnostic imaging; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson's disease; Peptide Fragments - administration & dosage; Peptide Fragments - metabolism; Rats; Rats, Sprague-Dawley; RVG29; Viral Proteins - administration & dosage; Viral Proteins - metabolism; N-3,4-bis(pivaloyloxy)-dopamine; RVG29; Brain targeting; Parkinson's disease; Liposomes
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2018.03.019

Parkinson's disease (PD) remains one of the most common neurodegenerative movement disorders with limited treatment options available. A dopamine derivative N-3,4-bis(pivaloyloxy)-dopamine (BPD) previously developed in our group has demonstrated superior therapeutic outcome compared to levodopa in a PD mice model. To further improve the therapeutic performance of BPD, a brain targeted drug delivery system was designed using a 29 amino-acid peptide (RVG29) derived from rabies virus glycoprotein as the targeting ligand. RVG29 functionalized liposomes (RVG29-lip) showed significantly higher uptake efficiency in murine brain endothelial cells and dopaminergic cells, and high penetration efficiency across the blood brain barrier (BBB) in vitro. In vivo and ex vivo distribution studies demonstrated RVG29-lip selectively distributed to the brain, striatum and substantia nigra. Furthermore, BPD loaded RVG29-lip (BPD-RVG29-lip) exhibited improved therapeutic efficacy in a PD mouse model, while causing no obvious systemic toxicity after intravenous administration. Thus, BPD-RVG29-lip represents a highly promising approach for the brain targeted treatment of PD. [Display omitted] •It’s the first time to design a brain targeted drug delivery system using dopamine derivative BPD for the treatment of PD;•The application of a brain targeted drug delivery system has improved the therapeutic performance of BPD;•The findings provide novel insights into the solutions to the druggability of small molecule drugs.•For the first time, RVG29 was used as a dual-targeting ligand for the treatment of PD.