title: On the mechanism of action of doxorubicin encapsulation in nanospheres for the reversal of multidrug resistance.
abstract: We had previously shown that doxorubicin encapsulation in polyisohexylcyanocrylate nanospheres could circumvent the P-glycoprotein-mediated multidrug resistance (MDR) exhibited by C6 rat glioblastoma in culture. We then investigated what could be the mechanism of such a circumvention. The cytotoxicity of free and encapsulated doxorubicin was evaluated in two MDR variants of the C6 cell line in a device allowing the separation of cells from drugs by a polycarbonate membrane of 0.2 micron pore size. We observed that the progressive disruption of the nanospheres allowed their doxorubicin content to reach the cell monolayer and exert its cytotoxicity in a fashion similar to that exhibited by free doxorubicin. However, no circumvention of MDR is obtained by doxorubicin encapsulation when drug-containing nanospheres are separated from the cells by the polycarbonate membrane. In addition, no effect on azidopine binding to P-glycoprotein-enriched membranes is exerted by unloaded nanospheres, even after their spontaneous degradation in cell-culture medium. Taken together, these results suggest that a physical contact between doxorubicin-containing nanospheres and the cells is required for the circumvention of MDR. The role of degradation products from the nanospheres as modulators of P-glycoprotein activity can be ruled out.
authors.affiliation: Institut Bergonié and Université de Bordeaux II, Bordeaux Cedex, France.
authors.forename: Y P
authors.initials: YP
authors.lastname: Hu
authors.forename: S
authors.initials: S
authors.lastname: Jarillon
authors.forename: C
authors.initials: C
authors.lastname: Dubernet
authors.forename: P
authors.initials: P
authors.lastname: Couvreur
authors.forename: J
authors.initials: J
authors.lastname: Robert
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D002470:Cell Survival / Q000187:drug effects; D003487:Cyanoacrylates; D004317:Doxorubicin / Q000008:administration & dosage*; D018432:Drug Resistance, Multiple; D005909:Glioblastoma; D008863:Microspheres; D051381:Rats; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D003487:Cyanoacrylates; C057532:polyisohexylcyanoacrylate; D004317:Doxorubicin