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The study was performed to investigate the potency of liposomal formulations to reduce or to overcome tamoxifen resistance. Therefore, estrogen receptor (ER) positive MCF-7 and ER deficient NCI/ADR cells with different sensitivity to tamoxifen were used. Instead of the parent compound, 4-hydroxytamoxifen (HT) was used as drug, because this metabolite is the most cytotoxic derivative in vitro. Liposomes further contained the membrane-active alkylphospholipid octadecyl-(1,1-dimethyl-piperidino-4-yl)-phosphate (OPP).Cellular uptake of HT during 3-24 h was determined by high performance thin layer chromatography technique (HPTLC). Free HT was taken up time independently by the two cell lines at 1.5-2.1 g HT/g cellular phosphate. Liposomal HT was taken up at a significantly higher degree than free HT in both cell lines, but the uptake was delayed in the sensitive MCF-7 cell line with the highest concentration detected after 24 h (3.5 g/g). Oppositely, the highest amount in the 'resistant' line (2.3 g/g) was already measured after 3 h in NCI/ADR cells. It successively decreased with incubation time.The faster uptake of liposomal HT by the NCI/ADR cells correlated with a stronger and earlier destruction of resistant NCI/ADR cells whereas the sensitive MCF-7 cells were mainly inhibited in their proliferation. Cytolytic effects were observed in both cell lines after extended incubation periods. The combination of HT with an alkylphospholipid further enhanced the cytotoxicity of the formulation. The IC50 in the NCI/ADR cells could be significantly reduced by liposomes combining both drugs to 15.1 μM compared with the IC50 of the free drugs (HT: 28.9 μM; OPP: 36.8 μM).It is assumed that the enhanced and accelerated uptake of liposomal HT in the cell line with relative drug resistance can increase the intracellular bioavailability of HT. The results of this study demonstrated that liposomes with encapsulated antiestrogen have a superior cytotoxic effect in resistant breast cancer cells. That coincided with the enhanced therapeutic effect of these vesicles observed in vivo.