Postacute ischemia vascular endothelial growth factor transfer by transferrin-targeted liposomes attenuates ischemic brain injury after experimental stroke in rats.
Our objective was to achieve the enhanced delivery of vascular endothelial growth factor (VEGF) to ischemically disordered brain through transferrin-coupled liposomes (Tf-PLs) via intravenous administration, and to observe the effect of Tf-VEGF-PLs on ischemic brain neuroprotection and angiogenesis. Cerebral VEGF overexpression was achieved with Tf-PLs by intravenous injection 48 hr after an acute stroke. β-Galactosidase expression was monitored; saline was injected as a control. The success of postischemic gene transduction was confirmed by β-galactosidase staining and by increased VEGF mRNA and protein in ischemic brain. Vascular density, neurological recovery, and ischemic area calculation were performed to evaluate the effect of Tf-VEGF-PLs. The positive expression of β-galactosidase indirectly indicated that VEGF was successfully delivered into brain by Tf-VEGF-PLs. VEGF mRNA in the Tf-VEGF-PL group 24 hr after injection was significantly higher than in the control group (p < 0.05). Western blot analysis showed that postischemic Tf-VEGF-PLs resulted in increased VEGF protein levels compared with VEGF-PLs and saline-administered rats (p < 0.05) 48 hr after administration. At 21 days after drug injection, we observed a significant decrease in infarct volume and better neurological function in the Tf-VEGF-PL-treated group, compared with the VEGF-PL group. FITC-dextran marking showed increased vascular density in the penumbra of Tf-VEGF-PL-treated hemispheres (245,873.9, number of microvessels per field) compared with that in VEGF-PL-treated hemispheres (139,801.3) or saline-treated hemispheres (102,175.5) (p < 0.05). The remainder of the cerebral blood flow after ischemia in the Tf-VEGF-PL group was significantly more than in the control groups (0.35 vs. 0.29, 0.21; p < 0.05). We conclude that the VEGF gene can be delivered noninvasively into the brain by Tf-VEGF-PLs. Postischemic treatment with Tf-VEGF-PLs effectively promoted neuroprotection and vascular regeneration in the chronic stage of cerebral infarction.
Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 5 Dongdan Santiao, Beijing, China. zh_zhaohao@yahoo.com.cn
Hao
H
Zhao
Xin-jie
XJ
Bao
Ren-zhi
RZ
Wang
Gui-lin
GL
Li
Jun
J
Gao
Si-hai
SH
Ma
Jun-ji
JJ
Wei
Ming
M
Feng
Ying-jie
YJ
Zhao
Wen-bin
WB
Ma
Yi
Y
Yang
Yong-ning
YN
Li
Yan-guo
YG
Kong
D000818:Animals; D001921:Brain / Q000098:blood supply*; D002545:Brain Ischemia / Q000473:pathology / Q000628:therapy*; D003911:Dextrans / Q000032:analysis; D004195:Disease Models, Animal; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000032:analysis; D015316:Genetic Therapy; D007275:Injections, Intravenous; D008081:Liposomes; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000473:pathology*; D014168:Transferrin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D001616:beta-Galactosidase / Q000378:metabolism
D003911:Dextrans; D008081:Liposomes; D018696:Neuroprotective Agents; D014168:Transferrin; D042461:Vascular Endothelial Growth Factor A; C015219:fluorescein isothiocyanate dextran; C467498:vascular endothelial growth factor A, rat; D001616:beta-Galactosidase; D016650:Fluorescein-5-isothiocyanate