FAILURE OF LIPOSOMAL ENCAPSULATION OF DOXORUBICIN TO CIRCUMVENT MULTIDRUG-RESISTANCE IN AN IN-VITRO MODEL OF RAT GLIOBLASTOMA CELLS

We studied the capacity of doxorubicin encapsulation in liposomes of v arious lipid compositions to circumvent multidrug resistance in severa l variants of the C6 rat glioblastoma cell line in culture, and to inh ibit azidopine binding to membranes isolated from these cells. Three f ormulations of liposomes were prepared: (a) phosphatidylcholine (PC)/p hosphatidylserine (PS)/cholesterol (cho) at a 9/2/4 ratio; (b) PC/card iolipin (CL)/cho at 10/1/4 ratio; (c) dipalmitoylphosphatidylcholine ( DPPC)/cho at 11/4 ratio. Unloaded liposomes presented no cytotoxicity against sensitive or resistant cells. Doxorubicin encapsulated in PC/P S/cho and PC/CL/cho liposomes had a cytotoxic activity close to that o f free doxorubicin, whereas doxorubicin encapsulated in DPPC/cho lipos omes was significantly less active than free doxorubicin in sensitive as well as in two of the three multidrug resistant cell lines, and as active as free doxorubicin in the third one. Free doxorubicin was able to decrease 50% of [H-3]azidopine photolabelling to P-glycoprotein at a concentration of 40 mu M; doxorubicin encapsulated in PC/CL/cho or PC/PS/cho liposomes was able to inhibit [H-3]azidopine binding similar ly as free drug, whereas doxorubicin encapsulated in DPPC/cho liposome s had no significant effect on this parameter. Unloaded liposomes of e ither lipid composition had no effect on [H-3]azidopine binding. Toget her with physical studies performed in parallel on doxorubicin trappin g in liposomes (J Liposome Res 1993, 3, 753-766), these results sugges t that doxorubicin leaked out of fluid; liposomes (PC/PS/cho or PC/CL/ cho), whereas rigid liposomes (DPPC/cho) were able to sequester the dr ug more efficiently. In that case, however, no availability of the dru g to the cells was possible and only a weak cytotoxicity was exhibited , especially without any favourable effect on multidrug resistance. In conclusion, no reversal of doxorubicin resistance was found to occur through liposomal encapsulation of the drug.