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

We have studied the cytotoxicity and accumulation of doxorubicin encap sulated in polyisohexylcyanoacrylate nanospheres in a model of doxorub icin-resistant rat glioblastoma variants differing by their degree of resistance to this drug. We observed that the particulate form of doxo rubicin was always more cytotoxic than free doxorubicin, whereas coadm inistration of drug-unloaded nanospheres with free doxorrbicin did not modify significantly doxorubicin cytotoxicity. In C6 0.001 cells, whi ch were 6-fold resistant and present a pure multidrug-resistant phenot ype, the reversal of doxorubicin resistance was complete. In C6 0.1 ce lls, which were 60-fold resistant, as with C6 1V cells (selected with vincristine), the reversal of doxorubicin resistance was almost comple te, with a residual resistance factor of 2-3. In C6 0.5 cells, which w ere 600-fold resistant to doxorubicin, the reversal of resistance was only partial and, in all cases, not above the expected participation o f P-glycoprotein to the phenotype of resistance. Intracellular drug ac cumulation after 2-h exposure to 17.2 mu mol/l doxorubicin was systema tically reduced by a factor of 2-3 when doxorubicin was incubated unde r the form of nanospheres; doxorubicin accumulation after a 2-h exposu re to IC50 was also highly reduced in all cell lines for doxorubicin-l oaded nanospheres. This work shows that association of doxorubicin wit h nanoparticles could provide a useful tool for circumventing multidru g resistance, probably by a bypass of P-glycoprotein rather than by an inhibition of this pump.