Interaction of Alkylphospholipid Formulations with Breast Cancer Cells in the Context of Anticancer Drug Development

Alkylphospholipids have shown promising results in several clinical studies (Mollinedo 2007) and among them Perifosine (octadecyl(1,1-di-methyl-4-piperidinium-4-yl)phosphate, OPP), and miltefosine (hexadecylphosphatidylcholine (HPC)) seems to be most promising for breast cancer therapy (Fichtner, Zeisig et al. 1994). For this type of tumor, an antitumor effect was found only for hormone receptor negative tumors in vivo, while no effect was found for receptor positive tumors. The reason for this difference is not yet understood and requires further studies. The exact mechanism of action of alkylphospholipids on the molecular level is still not well known in detail. It is clear that they do not target DNA, but they insert into the plasma membrane and subsequently induce a broad range of biological effects, ultimately leading to cell death. Unfortunately, administration of free (micellar) alkylphospholipids results in unwanted side effects, reflected in gastrointestinal toxicity and hemolytic activity, which limits the application of higher doses of alkylphospholipids. To achieve better therapeutic effects of alkylphospholipids in vivo with less side effects, different liposomal formulations of alkylphospholipids have been tested and showed diminished hemolytic activity. On the other hand, in most cases, cytotoxic activity of liposomes was also lower as compared to free alkylphospholipids (Zeisig et al., 1998). For efficient application of liposomes as nanocarriers in breast cancer therapy it is not only necessary to investigate the properties of the nanocarrier, which has to transport the drug to the (target) cell, but also the properties of the target cell. The main difference between Perifosine (OPP) resistent MCF7 cells and OPP sensitive MT-3 cells is in the uptake of OPP liposomes by cells and the transport of OPP across plasma membrane. At physiological temperatures the rate of transfer of OPP across plasma membrane increases to greater extent in OPP resistant MCF7 cells, while the uptake of liposomal OPP formulations is lower for