Up-regulating blood brain barrier permeability of nanoparticles via multivalent effect

Xihui Gao, Jun Qian, Shuyan Zheng, Ying Xiong, Jiahao Man, Binxin Cao, Lu Wang, Shenghong Ju, Cong Li

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Purpose: 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.

Original languageEnglish (US)
Pages (from-to)2538-2548
Number of pages11
JournalPharmaceutical Research
Issue number10
StatePublished - Oct 2013
Externally publishedYes


  • blood brain barrier
  • LRP receptor
  • multivalent effect
  • nanoparticle
  • receptor-mediated endocytosis

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Organic Chemistry
  • Molecular Medicine
  • Pharmacology (medical)
  • Biotechnology
  • Pharmacology


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