Paclitaxel- and lapatinib-loaded lipopolymer micelles overcome multidrug resistance in prostate cancer
Abstract
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 μM paclitaxel and 5 μM 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 μM paclitaxel was combined with lapatinib at a dose of 1 and 5 μM, 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 synerg...Continue Reading
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NMR study of the supramolecular structure of dual drug-loaded poly(butylcyanoacrylate) nanoparticles
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