Pluronic L61 Accelerates Flip–Flop and Transbilayer Doxorubicin Permeation

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Abstract
It has recently been found that Pluronics (block copolymers of ethylene oxide, EO, and propylene oxide, PO) favor the permeability and accumulation of anthracycline antibiotics, for example doxorubicin (Dox), in tumor cells. In an effort to understand these results, the interaction of EO2/PO32/EO2 (Pluronic L61) with unilamellar egg yolk vesicles (80–100 nm in diameter) was examined. A partition coefficient Kp=[Pl]membrane/[Pl]water=45 was determined. This corresponds to adsorption of about 20 polymer molecules to the surface of each vesicle in a 20 μM polymer solution. Despite this rather weak adsorption, Pluronic has a substantial effect upon the transmembrane permeation rate of Dox and upon the phospholipid flip–flop rate within the bilayers. Thus, the Dox permeation rate increases threefold and the flip–flop rate increases sixfold in 20 μM Pluronic. The two rates increase linearly with the amount of adsorbed polymer. The obvious ability of Pluronics to increase the mobility of membrane components may have important biomedical consequences.