Reversal of multidrug resistance to epirubicin by cyclosporin a in liposomes or intralipid

Clinical applications of the first-generation multidrug resistance (MDR) mo dulators, such as cyclosporin A (CsA) have been hampered because of their s evere side effects in vivo. In this study, we utilized liposomes and Intral ipid to provide selective delivery of CsA to tumor cell as well ns to circu mvent toxicities associated with CsA by altering the pharmacodistribution p roperties of encapsulated CsA. The MDR reversing effect of CsA in free, lip osomal ol Intralipid formulations on the uptake and transport of epirubicin in Caco-2 cells and rat intestines was evaluated. The results showed that CsA in free or liposomal formations significantly enhanced the intracellula r accumulation of epirubicin in a dose-related fashion in Caco-2 cells, wit h the highest enhancement at 2 muM: These formulations substantially amelio rated the apical to basolateral absorption of epirubicin in Caco-2 cells an d markedly increased mucosal to serosal absorption of epirubicin in mt jeju num and ileum. CsA in free, liposomal ol Intralipid formulations all signif icantly reduced basolateral to apical reflux of epirubicin across Caco-2 mo nolayers. CsA encapsulated in liposomes showed greater enhancement than oth er formulations. In conclusion, liposomal preparations of CsA may circumven t MDR and have the advantage of diminishing side effects, thus providing a useful alternative dosage form for intravenous administration of CsA to be combined with cytotoxic agents for the treatment of resistant tumours.