Vol. 303, Issue 3, 928-936, December 2002

Poly(ethylene glycol)-Coated Hexadecylcyanoacrylate Nanospheres Display a Combined Effect for Brain Tumor Targeting

Irène Brigger, Jackie Morizet, Geneviève Aubert, Hélène Chacun, Marie-José Terrier-Lacombe, Patrick Couvreur and Gilles Vassal

Laboratory of Biopharmacy and Pharmaceutical Technology, UMR Centre National de la Recherche Scientifique 8612, Faculty of Pharmacy, Châtenay-Malabry, France (I.B., H.C., P.C.), Laboratory of Pharmacology and New Treatments of Cancers, UPRES EA, Institut Gustave-Roussy, Villejuif, France (J.M., G.A., G.V.), Department of Anatomopathology, Institut Gustave-Roussy, Villejuif, France (M-J.T-L.), and Department of Pediatric Oncology, Institut Gustave-Roussy, Villejuif, France (G.V.)

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.