title: Targeting caspase-3 as dual therapeutic benefits by RNAi facilitating brain-targeted nanoparticles in a rat model of Parkinson's disease.
abstract: The activation of caspase-3 is an important hallmark in Parkinson's disease. It could induce neuron death by apoptosis and microglia activation by inflammation. As a result, inhibition the activation of caspase-3 would exert synergistic dual effect in brain in order to prevent the progress of Parkinson's disease. Silencing caspase-3 genes by RNA interference could inhibit the activation of caspase-3. We developed a brain-targeted gene delivery system based on non-viral gene vector, dendrigraft poly-L-lysines. A rabies virus glycoprotein peptide with 29 amino-acid linked to dendrigraft poly-L-lysines could render gene vectors the ability to get across the blood brain barrier by specific receptor mediated transcytosis. The resultant brain-targeted vector was complexed with caspase-3 short hairpin RNA coding plasmid DNA, yielding nanoparticles. In vivo imaging analysis indicated the targeted nanoparticles could accumulate in brain more efficiently than non-targeted ones. A multiple dosing regimen by weekly intravenous administration of the nanoparticles could reduce activated casapse-3 levels, significantly improve locomotor activity and rescue dopaminergic neuronal loss and in Parkinson's disease rats' brain. These results indicated the rabies virus glycoprotein peptide modified brain-targeted nanoparticles were promising gene delivery system for RNA interference to achieve anti-apoptotic and anti-inflammation synergistic therapeutic effects by down-regulation the expression and activation of caspase-3.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Yubo
authors.initials: Y
authors.lastname: Guo
authors.forename: Sai
authors.initials: S
authors.lastname: An
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Kuang
authors.forename: Xi
authors.initials: X
authors.lastname: He
authors.forename: Haojun
authors.initials: H
authors.lastname: Ma
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Jing
authors.initials: J
authors.lastname: Lv
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D053148:Caspase 3 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics; D008297:Male; D009043:Motor Activity / Q000502:physiology; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use; D010300:Parkinson Disease / Q000201:enzymology / Q000503:physiopathology / Q000628:therapy*; D010539:Permeability; D011107:Polylysine / Q000737:chemistry / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics; D011820:Rabies virus / Q000737:chemistry; D051381:Rats; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics
chemical_list: D006023:Glycoproteins; D034741:RNA, Small Interfering; D014764:Viral Proteins; D011107:Polylysine; D053148:Caspase 3