Investigation on mechanisms of glycopeptide nanoparticles for drug delivery across the blood-brain barrier

Nanomedicine (Lond). 2011 Apr;6(3):423-36. doi: 10.2217/nnm.11.11.


Aim: Nanoneuroscience, based on the use polymeric nanoparticles (NPs), represents an emerging field of research for achieving an effective therapy for neurodegenerative diseases. In particular, poly-lactide-co-glycolide (PLGA) glyco-heptapetide-conjugated NPs (g7-NPs) were shown to be able to cross the blood-brain barrier (BBB). However, the in vivo mechanisms of the BBB crossing of this kind of NP has not been investigated until now. This article aimed to develop a deep understanding of the mechanism of BBB crossing of the modified NPs.

Materials & methods: Loperamide and rhodamine-123 (model drugs unable to cross the BBB) were loaded into NPs, composed of a mixture of PLGA, differently modified with g7 or with a random sequence of the same aminoamids (random-g7). To study brain targeting of these model drugs, loaded NPs were administered via the tail vein in rats in order to perform both pharmacological studies and biodistribution analysis along with fluorescent, confocal and electron microscopy analysis, in order to achieve the NP BBB crossing mechanism. Computational analysis on the conformation of the g7- and random-g7-NPs of the NP surface was also developed.

Results: Only loperamide delivered to the brain with g7-NPs created a high central analgesia, corresponding to the 14% of the injected dose, and data were confirmed by biodistribution studies. Electron photomicrographs showed the ability of g7-NPs in crossing the BBB as evidenced by several endocytotic vesicles and macropinocytotic processes. The computational analysis on g7 and random-g7 showed a different conformation (linear vs globular), thus suggesting a different interaction with the BBB.

Conclusion: Taken together, this evidence suggested that g7-NP BBB crossing is enabled by multiple pathways, mainly membrane-membrane interaction and macropinocytosis-like mechanisms. The results of the computational analysis showed the Biousian structure of the g7 peptide, in contrast to random-g7 peptide (globular conformation), suggesting that this difference is pivotal in explaining the BBB crossing and allowing us to hypothesize regarding the mechanism of BBB crossing by g7-NPs.

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism*
  • Drug Delivery Systems*
  • Glycopeptides / administration & dosage*
  • Glycopeptides / chemistry
  • Lactic Acid / chemistry
  • Loperamide / administration & dosage
  • Loperamide / pharmacokinetics*
  • Male
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Neurodegenerative Diseases / drug therapy*
  • Polyglycolic Acid / chemistry
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Rats
  • Rats, Wistar
  • Rhodamine 123 / administration & dosage
  • Rhodamine 123 / pharmacokinetics*
  • Tissue Distribution


  • Glycopeptides
  • Rhodamine 123
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Polyglycolic Acid
  • Lactic Acid
  • Loperamide