Enhanced brain targeting efficiency of intranasally administered plasmid DNA: an alternative route for brain gene therapy.
Recently, nasal administration has been studied as a noninvasive route for delivery of plasmid DNA encoding therapeutic or antigenic genes. Here, we examined the brain targeting efficiency and transport pathways of intranasally administered plasmid DNA. Quantitative polymerase chain reaction (PCR) measurements of plasmid DNA in blood and brain tissues revealed that intranasally administered pCMVbeta (7.2 kb) and pN2/CMVbeta (14.1 kb) showed systemic absorption and brain distribution. Following intranasal administration, the beta-galactosidase protein encoded by these plasmids was significantly expressed in brain tissues. Kinetic studies showed that intranasally administered plasmid DNA reached the brain with a 2,595-fold higher efficiency than intravenously administered plasmid DNA did, 10 min post-dose. Over 1 h post-dose, the brain targeting efficiencies were consistently higher for intranasally administered plasmid DNA than for intravenously administered DNA. To examine how plasmid DNA enters the brain and moves to the various regions, we examined tissues from nine brain regions, at 5 and 10 min after intranasal or intravenous administration of plasmid DNA. Intravenously administered plasmid DNA displayed similar levels of plasmid DNA in the nine different regions, whereas, intranasally administered plasmid DNA exhibited different levels of distribution among the regions, with the highest plasmid DNA levels in the olfactory bulb. Moreover, plasmid DNA was mainly detected in the endothelial cells, but not in glial cells. Our results suggest that intranasally applied plasmid DNA may reach the brain through a direct route, possibly via the olfactory bulb, and that the nasal route might be an alternative method for efficiently delivering plasmid DNA to the brain.
Han
In-Kwon
IK
MyGene Bioscience Institute, Kangnam-gu, Seoul, South Korea.
Kim
Mi Young
MY
Byun
Hyang-Min
HM
Hwang
Tae Sun
TS
Kim
Jung Mogg
JM
Hwang
Kwang Woo
KW
Park
Tae Gwan
TG
Jung
Woon-Won
WW
Chun
Taehoon
T
Jeong
Gil-Jae
GJ
Oh
Yu-Kyoung
YK
D000281:Administration, Intranasal; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology; D004247:DNA / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004333:Drug Administration Routes; D018390:Gene Targeting; D015316:Genetic Therapy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009297:Nasal Mucosa / Q000276:immunology / Q000378:metabolism*; D009830:Olfactory Bulb / Q000378:metabolism; D010957:Plasmids / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution; D001616:beta-Galactosidase / Q000235:genetics / Q000493:pharmacokinetics
D012333:RNA, Messenger; D004247:DNA; D001616:beta-Galactosidase