Modulation of daunorubicin intracellular accumulation in P-glycoprotein expressing MCF-7 human breast adenocarcinoma cells by thermosensitive-liposome encapsulation and hyperthermia

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Abstract
Intracellular accumulation of free or thermosensitive liposome-encapsulated daunorubicin (TLED) at 37 or 43 degrees C, was evaluated using flow cytometry in chemosensitive and P-glycoprotein expressing MCF-7 human breast adenocarcinoma cells. At 37 degrees C, liposome-encapsulation significantly increased intracellular daunorubicin accumulation (IDA) in resistant cells (P=0.005) and that effect was statistically comparable to that achieved in adding 15 micromol/l verapamil to free daunorubicin (DNR). Combining TLED and verapamil further enhanced significantly (P=0.004) this effect as compared to TLED alone. However, none of these treatments restored IDA to the level achieved in sensitive cells. Hyperthermia significantly increased IDA in the sensitive cell (P<0.05), whenever free-DNR or TLED was used, but had no significant effect in the resistant cells, suggesting that P-glycoprotein could efflux the additional drug uptaken in hyperthermic conditions. In all these experiments combining the use of a modulator (verapamil or TLED) and hyperthermia, IDA was statistically comparable to that achieved with free-DNR in sensitive cells at 37 degrees C, but still remained lower than the IDA in sensitive cells at 43 degrees C (P<0.05). The results also showed that hyperthermia affected the labelling of P-glycoprotein by MRK16 monoclonal antibody.