Multidrug resistance (MDR) caused by high expression of
P-glycoprotein (Pgp) in
cancer patients remains one of the major obstacles to successful therapy of
cancer. Earlier studies have shown that the incorporation of Pgp-substrate drugs in
liposomes may provide a strategy to circumvent Pgp-mediated
drug efflux. The present study investigated the impact of
liposome composition on the efflux of Pgp-substrate incorporated in
liposomes.
Liposomes with varying compositions were loaded with
rhodamine 123, a
fluorescent probe frequently used as a Pgp-substrate, and the retention of
rhodamine was compared in two
breast cancer cell lines: wild-type cells with no detectable Pgp expression (MCF-7/WT) and Pgp-expressing cells resulting from stable transfection of the MDR1 gene (MCF-7/Pgp). Pgp-expression decreased the
rhodamine retention in MCF-7 cells, suggesting that Pgp is functional.
Liposome loading increased
rhodamine retention in MCF-7/Pgp cells, but not in MCF-7/WT cells. Surface charge of
liposomes did not affect the
rhodamine retention, whereas the incorporation of
cholesterol and polyethyleneglycol-attached
lipids was effective in further increasing the
rhodamine retention in MCF-7/Pgp cells. Since further study demonstrated that the rate of
rhodamine release from
liposomes tended to be inversely correlated with
rhodamine retention by cells, it seems likely that more rigid
liposomes are able to sequester
rhodamine more efficiently, thereby inhibiting direct interactions of
rhodamine with Pgp
proteins. Taken together, these findings suggest that Pgp-mediated MDR in
cancer cells may be more effectively modulated by optimizing the composition of
liposomes for loading Pgp-substrate anti-
cancer drugs.