title: Negative preclinical results with stealth nanospheres-encapsulated Doxorubicin in an orthotopic murine brain tumor model.
abstract: Previous results have shown that PEG-coated poly(hexadecylcyanoacrylate) (PEG-PHDCA) nanospheres displayed a significant accumulation within an orthotopic 9L gliosarcoma model, after i.v. administration to rats. Hence, the aim of the present study was to evaluate in the same model the pre-clinical efficacy of this carrier when loaded with Doxorubicin, an anticancer drug which poorly distributes in the CNS. Free and nanospheres-encapsulated Doxorubicin were administered with a multiple dose treatment. Their maximum tolerated dose (MTD) and increase in life span were respectively assessed in healthy and intracranially 9L-bearing rats. A comparative biodistribution study of Doxorubicin-loaded and unloaded PEG-PHDCA nanospheres was also performed in the tumor-bearing group. The results showed that the cumulative MTD of nanoparticulate doxorubicin was 1.5 times higher than this of free Doxorubicin. Nevertheless, encapsulated Doxorubicin was unable to elicit a better therapeutic response in the 9L gliosarcoma. Biodistribution study revealed that the Doxorubicin-loaded nanospheres accumulated to a 2.5-fold lesser extent in the 9L tumor as compared to the unloaded nanospheres and that they were mainly localized in the lungs and the spleen. Such a typical profile indicated aggregation with plasma proteins as a consequence of the positive surface charge of these loaded particles; this ionic interaction resulting from drug encapsulation was mainly responsible for 9L treatment failure.
authors.affiliation: Laboratory of Biopharmacy and Pharmaceutical Technology, UMR CNRS 8612, Faculty of Pharmacy, University of Paris-XI, 92296 Châtenay-Malabry, France. irene.guilbert@guerbet-group.com
authors.forename: Irène
authors.initials: I
authors.lastname: Brigger
authors.forename: Jackie
authors.initials: J
authors.lastname: Morizet
authors.forename: Lysiane
authors.initials: L
authors.lastname: Laudani
authors.forename: Geneviève
authors.initials: G
authors.lastname: Aubert
authors.forename: Martine
authors.initials: M
authors.lastname: Appel
authors.forename: Valérie
authors.initials: V
authors.lastname: Velasco
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Terrier-Lacombe
authors.forename: Didier
authors.initials: D
authors.lastname: Desmaële
authors.forename: Jean
authors.initials: J
authors.lastname: d'Angelo
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*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018316:Gliosarcoma / Q000188:drug therapy*; D007150:Immunohistochemistry; D008297:Male; D020714:Maximum Tolerated Dose; D043942:Nanotubes; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
chemical_list: D004317:Doxorubicin