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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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 various lipid compositions to circumvent multidrug resistance in several variants of the C6 rat glioblastoma cell line in culture, and to inhibit azidopine binding to membranes isolated from these cells. Three formulations of liposomes were prepared: (a) phosphatidylcholine (PC)/phosphatidylserine (PS)/cholesterol (cho) at a 9/24 ratio; (b) PC/cardiolipin (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/PS/cho and PC/CL/cho liposomes had a cytotoxic activity close to that of free doxorubicin, whereas doxorubicin encapsulated in DPPC/cho liposomes 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 [3H]azidopine photolabelling to P-glycoprotein at a concentration of 40 microM; doxorubicin encapsulated in PC/CL/cho or PC/PS/cho liposomes was able to inhibit [3H]azidopine binding similarly as free drug, whereas doxorubicin encapsulated in DPPC/cho liposomes had no significant effect on this parameter. Unloaded liposomes of either lipid composition had no effect on [3H]azidopine binding. Together with physical studies performed in parallel on doxorubicin trapping in liposomes (J Liposome Res 1993, 3, 753-766), these results suggest that doxorubicin leaked out of fluid liposomes (PC/PS/cho or PC/CL/cho), whereas rigid liposomes (DPPC/cho) were able to sequester the drug more efficiently. In that case, however, no availability of the drug 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.[1]


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