On the mechanism of action of doxorubicin encapsulation in nanospheres for the reversal of multidrug resistance

Cancer Chemother Pharmacol. 1996;37(6):556-60. doi: 10.1007/s002800050428.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / administration & dosage*
  • Cell Survival / drug effects
  • Cyanoacrylates
  • Doxorubicin / administration & dosage*
  • Drug Resistance, Multiple*
  • Glioblastoma
  • Microspheres
  • Rats
  • Tumor Cells, Cultured


  • Antibiotics, Antineoplastic
  • Cyanoacrylates
  • polyisohexylcyanoacrylate
  • Doxorubicin