title: Up-regulating blood brain barrier permeability of nanoparticles via multivalent effect.
abstract: OBJECTIVE
  To investigate the multivalent effect for up-regulating the intracerebral delivery of nanoparticles via receptor-mediated transcytosis.
  
  
  METHODS
  Nanoparticles labeled with near-infrared (NIR) fluorophore and different numbers of angiopep-2 peptides that specifically target low-density lipoprotein receptor-related protein (LRP) on the brain capillary endothelial cells were developed. Bio-distribution studies quantified the intracerebral uptakes of these nanoparticles at 2 and 24 h after intravenous injection. In vivo NIR fluorescence imaging, ex vivo autoradiographic imaging and 3D reconstructed NIR fluorescence imaging revealed the nanoparticle distribution pattern in brain. Fluorescence microscopic imaging identified the nanoparticle locations at the cellular level.
  
  
  RESULTS
  The multimetirc association between the angiopep-2 peptides labeled on the nanoparticle and the LRP receptors on the brain capillary endothelial cells significantly increased the intracerebral uptake of the nanoparticles. Nanoparticle Den-Angio4 labeled four angiopep-2 peptides achieved the highest BBB traverse efficacy. After penetrating the BBB, Den-Angio4 distributed heterogeneously and mainly located at hippocampus, striatum and cerebellum in the brains.
  
  
  CONCLUSIONS
  The multivalent effect significantly enhances the BBB permeability of nanoparticles. Den-Angio4 as a nanoparticle prototype provides a two order targeted strategy for diagnosis or treatment of central nerver system diseases by first traversing the BBB via receptor-mediated endocytosis and secondly targeting the leisions with high receptor expression level.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA School of Pharmacy, Fudan University, Shanghai, 201203, China.
authors.forename: Xihui
authors.initials: X
authors.lastname: Gao
authors.forename: Jun
authors.initials: J
authors.lastname: Qian
authors.forename: Shuyan
authors.initials: S
authors.lastname: Zheng
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.forename: Jiahao
authors.initials: J
authors.lastname: Man
authors.forename: Binxin
authors.initials: B
authors.lastname: Cao
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Shenghong
authors.initials: S
authors.lastname: Ju
authors.forename: Cong
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002533:Cerebral Angiography; D050091:Dendrimers / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D010539:Permeability; D014018:Tissue Distribution; D057900:Transcytosis / Q000502:physiology*
chemical_list: C531860:Angiopep-2; D050091:Dendrimers; D004337:Drug Carriers; D026502:LDL-Receptor Related Proteins; C104700:PAMAM Starburst; D010455:Peptides