It was reported previously that tamoxifen （TAM） could increase the intracellular accumulation of drug-loaded liposomes, but the exact mechanism is unknown although it was supposed that TAM might enhance the cell uptake by inhibiting the drug efflux caused by P-glycoprotein （P-gp）. To identify the mechanism of increased cellular uptake of liposomes induced by tamoxifen, PEGgylated liposomes （SSL） ofP-gp-substrate doxorubicin （DOX） or non-P-gp-substrate coumarin （Cou） were prepared with or without TAM. The cell uptake of these liposome systems was investigated in cell lines with different P-gp-expressing levels and the interaction of TAM with lipid membrane was also studied. As the results, the co-encapsulation of TAM with DOX-SSL increased the intracellular uptake in all three tumor cell lines. In P-gp-highly-expressing MCF-7/Adr cells, the effect of TAM was the strongest and in negative control Hela cells, the impact weakened but still significant. The improvement was also observed in the cellular uptake of Cou-SSL. Surface plasmon resonance （SPR） studies demonstrated that TAM-SSL exhibited a much stronger atYmity with model biomembrane compared with empty SSL, and ft^her test with isothermal titration calorimetry （ITC） showed that free TAM had an obvious interaction with lipid membrane. In conclusion, TAM could increase the affinity of liposomes with biomembrane and enhance the intracellular accumulation of liposomes via both TAM-mediated P-gp inhibition and the increased interaction between hydrophobic TAM molecules and lipid membrane.
