Angiopep-Conjugated Nanoparticles for Targeted Long-Term Gene Therapy of Parkinson’s Disease

Author: Huang Rongqin   Ma Haojun   Guo Yubo   Liu Shuhuan   Kuang Yuyang   Shao Kun   Li Jianfeng   Liu Yang   Han Liang   Huang Shixian   An Sai   Ye Liya   Lou Jinning   Jiang Chen  

Publisher: Springer Publishing Company

ISSN: 0724-8741

Source: Pharmaceutical Research, Vol.30, Iss.10, 2013-10, pp. : 2549-2559

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Abstract

To prepare an angiopep-conjugated dendrigraft poly-L-lysine (DGL)-based gene delivery system and evaluate the neuroprotective effects in the rotenone-induced chronic model of Parkinson’s disease (PD).Angiopep was applied as a ligand specifically binding to low-density lipoprotein receptor-related protein (LRP) which is overexpressed on blood-brain barrier (BBB), and conjugated to biodegradable DGL via hydrophilic polyethyleneglycol (PEG), yielding DGL-PEG-angiopep (DPA). In vitro characterization was carried out. The neuroprotective effects were evaluated in a chronic parkinsonian model induced by rotenone using a regimen of multiple dosing intravenous administrations.The successful synthesis of DPA was demonstrated via 1H-NMR. After encapsulating the therapeutic gene encoding human glial cell line-derived neurotrophic factor (hGDNF), DPA/hGDNF NPs showed a sphere-like shape with the size of 119 ± 12 nm and zeta potential of 8.2 ± 0.7 mV. Angiopep-conjugated NPs exhibited higher cellular uptake and gene expression in brain cells compared to unmodified counterpart. The pharmacodynamic results showed that rats in the group with five injections of DPA/hGDNF NPs obtained best improved locomotor activity and apparent recovery of dopaminergic neurons compared to those in other groups.This work provides a practical non-viral gene vector for long-term gene therapy of chronic neurodegenerative disorders.