Ability of doxorubicin-loaded nanoparticles to overcome multidrug resistance of tumor cells after their capture by macrophages

Purpose. Investigation of the ability of doxorubicin-loaded nanoparticles ( NP/Dox) to overcome multidrug resistance (MDR) when they have first been ta ken up by macrophages. Methods. The growth inhibition of P388 sensitive (P388) and resistant (P388 /ADR) tumor cells was evaluated in a coculture system consisting of wells w ith two compartments. The tumor cells were seeded into the lower compartmen t, the macrophages were introduced into the upper part in which the drug pr eparations were also added. Results. Doxorubicin exerted lower cytotoxicity on tumor cells in coculture compared with direct contact. In P388/ADR, NP/Dox cytotoxicity was far hig her than that of free doxorubicin (Dox). Three different formulations of cy closporin A (either free (CyA), loaded to nanoparticles (NP/CyA) or in a co mbined formulation with doxorubicin (NP/Dox-CyA)), were added to modulate d oxorubicin efficacy. The addition of cyclosporin A to Dox increased drug cy totoxicity. Both CyA added to NP/Dox and NP/Dox-CyA were able to bypass dru g resistance. Conclusions. Despite the barrier role of macrophages, NP/Dox remained far m ore cytotoxic than Dox against P388/ADR. Both NP/Dox + CyA and NP/Dox-CyA a llowed to overcome MDR, but the last one should present greater advantage i ll vivo by confining both drugs in the same compartment, hence reducing the adverse effects.