TY - JOUR
T1 - Negative preclinical results with stealth® nanospheres-encapsulated Doxorubicin in an orthotopic murine brain tumor model
AU - Brigger, Irène
AU - Morizet, Jackie
AU - Laudani, Lysiane
AU - Aubert, Geneviève
AU - Appel, Martine
AU - Velasco, Valérie
AU - Terrier-Lacombe, Marie Josée
AU - Desmaële, Didier
AU - D'Angelo, Jean
AU - Couvreur, Patrick
AU - Vassal, Gilles
N1 - Funding Information:
This work was supported by grants ARC no. 5837 and 4406 from the Association pour la Recherche sur le Cancer, France.
PY - 2004/11/5
Y1 - 2004/11/5
N2 - 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.
AB - 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.
KW - 9L gliosarcoma
KW - Biodistribution
KW - Doxorubicin
KW - PEG-coated poly(cyanoacrylate) nanospheres
KW - Preclinical evaluation
UR - http://www.scopus.com/inward/record.url?scp=7444256573&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2004.07.019
DO - 10.1016/j.jconrel.2004.07.019
M3 - Article
AN - SCOPUS:7444256573
SN - 0168-3659
VL - 100
SP - 29
EP - 40
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 1
ER -