title: Investigation on mechanisms of glycopeptide nanoparticles for drug delivery across the blood-brain barrier.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Modena & Reggio Emilia, Via Campi, 41100 Modena, Italy. tosi.giovanni@unimore.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tosi
authors.forename: Rita Adriana
authors.initials: RA
authors.lastname: Fano
authors.forename: Lucia
authors.initials: L
authors.lastname: Bondioli
authors.forename: Luca
authors.initials: L
authors.lastname: Badiali
authors.forename: Rois
authors.initials: R
authors.lastname: Benassi
authors.forename: Francesco
authors.initials: F
authors.lastname: Rivasi
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruozi
authors.forename: Flavio
authors.initials: F
authors.lastname: Forni
authors.forename: Maria Angela
authors.initials: MA
authors.lastname: Vandelli
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D016503:Drug Delivery Systems; D006020:Glycopeptides / Q000008:administration & dosage* / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry; D008139:Loperamide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123 / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D006020:Glycopeptides; D020112:Rhodamine 123; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D008139:Loperamide