Negative preclinical results with stealth nanospheres-encapsulated Doxorubicin in an orthotopic murine brain tumor model.
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.
Brigger
Irène
I
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
Morizet
Jackie
J
Laudani
Lysiane
L
Aubert
Geneviève
G
Appel
Martine
M
Velasco
Valérie
V
Terrier-Lacombe
Marie-Josée
MJ
Desmaële
Didier
D
d'Angelo
Jean
J
Couvreur
Patrick
P
Vassal
Gilles
G
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
D004317:Doxorubicin