Paclitaxel- and lapatinib-loaded lipopolymer micelles overcome multidrug resistance in prostate cancer

Paclitaxel is a potent chemotherapeutic agent for treating refractory prostate cancer. However, its prolonged treatment develops multidrug resistance. Since lapatinib interacts with and inhibits P-gp activity, our objective was to determine whether the combination therapy of these two drugs can synergistically treat resistant prostate cancer. Our recently synthesized lipopolymer, poly(ethylene glycol)-block-poly(2-methyl-2-carboxylpropylene carbonate-graft-dodecanol) (PEG-PCD), was used to efficiently load both drugs into PEG-PCD micelles since they are hydrophobic. Lapatinib inhibited P-gp function but not its expression. Co-treatment of DU145-TXR cells with 0.5 mu M paclitaxel and 5 mu M lapatinib resulted in up to 138-fold reversal compared to paclitaxel alone. These formulations killed almost 70% and 80% of DU145-TXR cells when 0.5 mu M paclitaxel was combined with lapatinib at a dose of 1 and 5 mu M, respectively, while monotherapy had no effect. Combination therapy induced apoptosis and cell cycle arrest at mitotic phase. Xenograft tumor growth in athymic nude mice was significantly regressed when PEG-PCD micelles carrying lapatinib and paclitaxel were given intravenously twice a week. Furthermore, this combination therapy synergistically decreased antiangiogenic activity compared to the control or their monotherapy. In conclusion, lipopolymeric micelles carrying lapatinib and paclitaxel have the potential to treat resistant prostate cancer and can successfully deliver drugs to tumors while minimizing toxic effects associated with solubilizing agents.