Paclitaxel- and lapatinib-loaded lipopolymer micelles overcome multidrug resistance in prostate cancer
Paclitaxel- and lapatinib-loaded lipopolymer micelles overcome multidrug resistance in prostate cancer
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DOI：
10.1007/s13346-011-0042-2
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发表时间：
2011-12-01
影响因子：
5.4
通讯作者：
Mahato, Ram I.
中科院分区：
文献类型：
--
作者：
Li, Feng;Danquah, Michael;Mahato, Ram I.
紫杉醇是治疗难治性前列腺癌的有效化疗药物。然而，长期治疗会产生多药耐药性。由于拉帕替尼与P-gp相互作用并抑制P-gp活性，我们的目的是确定这两种药物的联合治疗是否可以协同治疗耐药前列腺癌。我们最近合成的脂质聚合物，聚（乙二醇）-嵌段-聚（2-甲基-2-羧基丙烯碳酸酯-接枝-十二烷醇）（PEG-PCD），被用来有效地加载两种药物到PEG-PCD胶束，因为它们是疏水性的。拉帕替尼抑制P-gp功能，但不抑制其表达。用0.5 μ M紫杉醇和5 μ M拉帕替尼共同处理DU 145-TXR细胞，与单独使用紫杉醇相比，逆转率高达138倍。当0.5 μ M紫杉醇分别以1和5 μ M剂量与拉帕替尼联合使用时，这些制剂杀死了几乎70%和80%的DU 145-TXR细胞，而单一疗法没有效果。联合治疗诱导细胞凋亡和细胞周期阻滞在有丝分裂期。当每周两次静脉内给予携带拉帕替尼和紫杉醇的PEG-PCD胶束时，无胸腺裸鼠中的异种移植肿瘤生长显著消退。此外，与对照或其单一疗法相比，该组合疗法协同降低抗血管生成活性。总之，携带拉帕替尼和紫杉醇的脂聚合物胶束具有治疗耐药前列腺癌的潜力，并且可以成功地将药物递送至肿瘤，同时最小化与增溶剂相关的毒性作用。
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.