title: Tat peptide-decorated gelatin-siloxane nanoparticles for delivery of CGRP transgene in treatment of cerebral vasospasm.
abstract: BACKGROUND
  Gene transfer using a nanoparticle vector is a promising new approach for the safe delivery of therapeutic genes in human disease. The Tat peptide-decorated gelatin-siloxane (Tat-GS) nanoparticle has been demonstrated to be biocompatible as a vector, and to have enhanced gene transfection efficiency compared with the commercial reagent. This study investigated whether intracisternal administration of Tat-GS nanoparticles carrying the calcitonin gene-related peptide (CGRP) gene can attenuate cerebral vasospasm and improve neurological outcomes in a rat model of subarachnoid hemorrhage.
  
  
  METHODS
  A series of gelatin-siloxane nanoparticles with controlled size and surface charge was synthesized by a two-step sol-gel process, and then modified with the Tat peptide. The efficiency of Tat-GS nanoparticle-mediated gene transfer of pLXSN-CGRP was investigated in vitro using brain capillary endothelial cells and in vivo using a double-hemorrhage rat model. For in vivo analysis, we delivered Tat-GS nanoparticles encapsulating pLXSN-CGRP intracisternally using a double-hemorrhage rat model.
  
  
  RESULTS
  In vitro, Tat-GS nanoparticles encapsulating pLXSN-CGRP showed 1.71 times higher sustained CGRP expression in endothelial cells than gelatin-siloxane nanoparticles encapsulating pLXSN-CGRP, and 6.92 times higher CGRP expression than naked pLXSN-CGRP. However, there were no significant differences in pLXSN-CGRP entrapment efficiency and cellular uptake between the Tat-GS nanoparticles and gelatin-siloxane nanoparticles. On day 7 of the in vivo experiment, the data indicated better neurological outcomes and reduced vasospasm in the subarachnoid hemorrhage group that received Tat-GS nanoparticles encapsulating pLXSN-CGRP than in the group receiving Tat-GS nanoparticles encapsulating pLXSN alone because of enhanced vasodilatory CGRP expression in cerebrospinal fluid.
  
  
  CONCLUSIONS
  Overexpression of CGRP attenuated vasospasm and improved neurological outcomes in an experimental rat model of subarachnoid hemorrhage. Tat-GS nanoparticle-mediated CGRP gene delivery could be an innovative strategy for treatment of cerebral vasospasm after subarachnoid hemorrhage.
authors.affiliation: Department of Neurosurgery, Zhongshan Hospital, Xiamen University, Xiamen, People's Republic of China. txhmd@yahoo.com.cn
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Tian
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Wang
authors.forename: Han
authors.initials: H
authors.lastname: Meng
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.forename: Feng
authors.initials: F
authors.lastname: Wei
authors.forename: Zhi-Chun
authors.initials: ZC
authors.lastname: Huang
authors.forename: Xiao-Ning
authors.initials: XN
authors.lastname: Lin
authors.forename: Lei
authors.initials: L
authors.lastname: Ren
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D015740:Calcitonin Gene-Related Peptide / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells; D005780:Gelatin / Q000008:administration & dosage / Q000737:chemistry*; D006801:Humans; D008297:Male; D053769:Nanocapsules / Q000008:administration & dosage*; D010316:Particle Size; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012833:Siloxanes / Q000008:administration & dosage / Q000737:chemistry*; D013345:Subarachnoid Hemorrhage / Q000378:metabolism; D013346:Subarachnoid Space / Q000098:blood supply / Q000473:pathology; D014162:Transfection / Q000379:methods; D019076:Transgenes; D020301:Vasospasm, Intracranial / Q000628:therapy*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism
chemical_list: D053769:Nanocapsules; D012833:Siloxanes; D054322:tat Gene Products, Human Immunodeficiency Virus; D005780:Gelatin; D015740:Calcitonin Gene-Related Peptide
keywords: calcitonin gene-related peptide; cerebral vasospasm; gene transfer; nanoparticles