title: Poly(ethylene glycol)-coated hexadecylcyanoacrylate nanospheres display a combined effect for brain tumor targeting.
abstract: The aim of the present study was to evaluate the tumor accumulation of radiolabeled long-circulating poly(ethylene glycol) (PEG)-coated hexadecylcyanoacrylate nanospheres and non-PEG-coated hexadecylcyanoacrylate nanospheres (used as control), after intravenous injection in Fischer rats bearing intracerebrally well established 9L gliosarcoma. Both types of nanospheres showed an accumulation with a retention effect in the 9L tumor. However, long-circulating nanospheres concentrated 3.1 times higher in the gliosarcoma, compared with non-PEG-coated nanospheres. The tumor-to-brain ratio of pegylated nanospheres was found to be 11, which was in accordance with the ratios reported for other carriers tested for brain tumor targeting such as long-circulating liposomes or labels for magnetic resonance imaging. In addition, a 4- to 8-fold higher accumulation of the PEG-coated carriers was observed in normal brain regions, when compared with control nanospheres. Using a simplified pharmacokinetic model, two different mechanisms were proposed to explain this higher concentration of PEG-coated nanospheres in a tumoral brain. 1) in the 9L tumor, the preferential accumulation of pegylated nanospheres was attributable to their slower plasma clearance, relative to control nanospheres. Diffusion/convection was the proposed mechanism for extravasation of the nanospheres in the 9L interstitium, across the altered blood-brain barrier. 2) In addition, PEG-coated nanospheres displayed an affinity with the brain endothelial cells (normal brain region), which may not be considered as the result of a simple diffusion/convection process. The exact underlying mechanism of such affinity deserves further investigation, since it was observed to be as important as specific interactions described for immunoliposomes with the blood-brain barrier.
authors.affiliation: Laboratory of Biopharmacy and Pharmaceutical Technology, UMR Centre National de la Recherche Scientifique 8612, Faculty of Pharmacy, Châtenay-Malabry, France.
authors.forename: Irène
authors.initials: I
authors.lastname: Brigger
authors.forename: Jackie
authors.initials: J
authors.lastname: Morizet
authors.forename: Geneviève
authors.initials: G
authors.lastname: Aubert
authors.forename: Hélène
authors.initials: H
authors.lastname: Chacun
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Terrier-Lacombe
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D003487:Cyanoacrylates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods*; D018316:Gliosarcoma / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008863:Microspheres; D036103:Nanotechnology / Q000379:methods*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D003487:Cyanoacrylates; D011092:Polyethylene Glycols