期刊
PHARMACEUTICAL RESEARCH
卷 30, 期 10, 页码 2549-2559出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-013-1005-8
关键词
angiopep-conjugated nanoparticles; dendrigraft poly-L-lysine; gene therapy; multiple dosing administrations; Parkinson's disease
资金
- Specialized Research Fund for Doctoral Program [20090071120066]
- Fudan University
- Shanghai Municipal Education Commission
- Shanghai Education Development Foundation
- National Key Basic Research Program of China (973 Program) [2013CB932502]
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 H-1-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.
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