title: Angiopep-conjugated nanoparticles for targeted long-term gene therapy of Parkinson's disease.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  The successful synthesis of DPA was demonstrated via (1)H-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.
  
  
  CONCLUSIONS
  This work provides a practical non-viral gene vector for long-term gene therapy of chronic neurodegenerative disorders.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
authors.forename: Rongqin
authors.initials: R
authors.lastname: Huang
authors.forename: Haojun
authors.initials: H
authors.lastname: Ma
authors.forename: Yubo
authors.initials: Y
authors.lastname: Guo
authors.forename: Shuhuan
authors.initials: S
authors.lastname: Liu
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Kuang
authors.forename: Kun
authors.initials: K
authors.lastname: Shao
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.forename: Shixian
authors.initials: S
authors.lastname: Huang
authors.forename: Sai
authors.initials: S
authors.lastname: An
authors.forename: Liya
authors.initials: L
authors.lastname: Ye
authors.forename: Jinning
authors.initials: J
authors.lastname: Lou
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D008297:Male; D058726:Nanoconjugates / Q000737:chemistry*; D010300:Parkinson Disease / Q000235:genetics / Q000628:therapy*; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: C531860:Angiopep-2; D051100:Glial Cell Line-Derived Neurotrophic Factor; D026502:LDL-Receptor Related Proteins; D058726:Nanoconjugates; D010455:Peptides