Neuroprotection in a 6-hydroxydopamine-lesioned Parkinson model using lactoferrin-modified nanoparticles.
BACKGROUND
Nonviral gene therapy of chronic degenerative diseases such as Parkinson's disease (PD) is a great challenge as a result of the low tranfection efficiency of nonviral gene vectors. We previously constructed a lactoferrin (Lf)-modified vector, which was demonstrated to be potential for brain gene delivery both in vitro and in vivo. In the present study, this type of vector was applied to load human glial cell line-derived neurotrophic factor gene (hGDNF).


METHODS
A rat PD model was constructed by the unilateral lesion of striatum using 6-hydroxydopamine (6-OHDA). Lf-modified nanoparticles (NPs) were prepared and characterized. Neuroprotective effects of Lf-modified NPs were examined in the 6-OHDA-lesioned PD model via a regimen of multiple dosing intravenous administrations.


RESULTS
The size of Lf-modified NPs was 196 +/- 10.1 nm, whereas the zeta potential value was 29.35 +/- 3.27 mV. Lf-modified NPs could protect themselves from heparin displacement and DNase digestion. The results of the neuroprotective evaluation show that increasing the number of injections of Lf-modified NPs loading hGDNF improved locomotor activity, reduced dopaminergic neuronal loss and enhanced monoamine neurotransmitter levels in PD rats. Five injections of Lf-modified NPs loading hGDNF exhibited much more powerful neuroprotection than a single injection, indicating the effectiveness and feasibility of multiple dosing administrations. The results of toxicity tests demonstrated that the dosage of NPs used in the present study was safe enough for brain gene delivery.


CONCLUSIONS
The findings obtained in the present study suggest that Lf-modified NPs could be developed for potential nonviral gene therapy of chronic brain disorders.
Huang
Rongqin
R
Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, China.
Han
Liang
L
Li
Jianhua
J
Ren
Feiliang
F
Ke
Weilun
W
Jiang
Chen
C
Pei
Yuanying
Y
D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D015316:Genetic Therapy; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics; D007150:Immunohistochemistry; D007781:Lactoferrin / Q000737:chemistry*; D008297:Male; D053758:Nanoparticles; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000517:prevention & control / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley
D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D016627:Oxidopamine; D007781:Lactoferrin