ENHANCED CYTOTOXICITY OF DOXORUBICIN ENCAPSULATED IN POLYISOHEXYLCYANOACRYLATE NANOSPHERES AGAINST MULTIDRUG-RESISTANT TUMOR-CELLS IN CULTURE

We have studied the cytotoxicity and accumulation of doxorubicin encapsulated in polyisohexylcyanoacrylate nanospheres in a model of doxorubicin-resistant rat glioblastoma variants differing by their degree of resistance to this drug. We observed that the particulate form of doxorubicin was always more cytotoxic than free doxorubicin, whereas coadministration of drug-unloaded nanospheres with free doxorrbicin did not modify significantly doxorubicin cytotoxicity. In C6 0.001 cells, which were 6-fold resistant and present a pure multidrug-resistant phenotype, the reversal of doxorubicin resistance was complete. In C6 0.1 cells, which were 60-fold resistant, as with C6 1V cells (selected with vincristine), the reversal of doxorubicin resistance was almost complete, with a residual resistance factor of 2-3. In C6 0.5 cells, which were 600-fold resistant to doxorubicin, the reversal of resistance was only partial and, in all cases, not above the expected participation of P-glycoprotein to the phenotype of resistance. Intracellular drug accumulation after 2-h exposure to 17.2 mu mol/l doxorubicin was systematically reduced by a factor of 2-3 when doxorubicin was incubated under the form of nanospheres; doxorubicin accumulation after a 2-h exposure to IC50 was also highly reduced in all cell lines for doxorubicin-loaded nanospheres. This work shows that association of doxorubicin with nanoparticles could provide a useful tool for circumventing multidrug resistance, probably by a bypass of P-glycoprotein rather than by an inhibition of this pump.