title: Cell-penetrating peptide-modified block copolymer micelles promote direct brain delivery via intranasal administration.
abstract: OBJECTIVE
  In order to develop non-invasive and effective nose-to-brain delivery of drugs, we synthesized Tat analog-modified methoxy poly(ethylene glycol) (MPEG)/poly(ε-caprolactone) (PCL) amphiphilic block copolymers through the ester bond.
  
  
  METHODS
  We evaluated the brain distribution of coumarin, acting as a model chemical, after intravenous or intranasal administration of MPEG-PCL. In addition, cellular uptake of coumarin by rat glioma cells transfected with coumarin-loaded MPEG-PCL or MPEG-PCL-Tat was determined. Finally, we determined the brain distribution and biodistribution after intranasal administration of coumarin-loaded MPEG-PCL-Tat.
  
  
  RESULTS
  The amount of coumarin in the brain after intranasal administration was significantly higher than that after intravenous administration. In addition, cellular uptake of coumarin using MPEG-PCL was the lowest, while cellular uptake of coumarin using Tat-modified MPEG-PCL (MPEG-PCL-Tat) was higher than that of MPEG-PCL. Therefore, the brain distribution of coumarin administered using MPEG-PCL-Tat was significantly greater than that using MPEG-PCL. Then, the coumarin distribution after MPEG-PCL-Tat administration in non-targeted tissues (lung, liver, heart, kidney and spleen) was lower than that after coumarin administration without nanomicelles.
  
  
  CONCLUSIONS
  We have demonstrated that utilization of nano-sized micelles modified with Tat can facilitate direct intranasal brain delivery.
authors.affiliation: Laboratory of Pharmaceutics and Drug Delivery Department of Pharmaceutical Science, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. kanazawa@toyaku.ac.jp
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanazawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Taki
authors.forename: Ko
authors.initials: K
authors.lastname: Tanaka
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Takashima
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okada
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry*; D003374:Coumarins / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D005910:Glioma / Q000378:metabolism; D007275:Injections, Intravenous; D008823:Micelles; D009368:Neoplasm Transplantation; D010316:Particle Size; D010446:Peptide Fragments / Q000737:chemistry*; D011091:Polyesters / Q000138:chemical synthesis / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry*
chemical_list: D057846:Cell-Penetrating Peptides; D003374:Coumarins; D004337:Drug Carriers; D008823:Micelles; D010446:Peptide Fragments; D011091:Polyesters; C439611:methoxy poly(ethylene glycol-co-epsilon-caprolactone); D054322:tat Gene Products, Human Immunodeficiency Virus; C520542:tat peptide (48-57), Human immunodeficiency virus 1; D011092:Polyethylene Glycols; C030123:coumarin