Modulation of doxorubicin resistance in multidrug-resistance cells by targeted liposomes combined with hyperthermia.
Modulation of doxorubicin resistance in multidrug-resistance cells by targeted liposomes combined with hyperthermia.
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DOI：
10.1080/10258140290033066
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发表时间：
2002-10-01
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影响因子：
--
通讯作者：
Gaber, Mohamed H
中科院分区：
文献类型：
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作者：
Gaber, Mohamed H
用于克服多药耐药性（MDR）的传统方法通常涉及化学增敏剂和抗癌药物的共同给药。然而，许多化学增敏剂与抗癌药物（例如阿霉素（Dox））的共同给药导致抗癌药物毒性加剧。在这里，我们假设使用脂质体载体、合适的靶向部分和热疗等物理因素来优化抗癌药物递送，在 MDR 癌细胞的治疗中具有显着的优势。由于维生素叶酸受体经常在上皮癌细胞上过度表达，因此我们使用叶酸作为针对两种类型细胞系的靶向部分，即人宫颈癌衍生的 KB-31 (KB31) 和耐药型 KB-85 (KB85)。通过将 1 mol% 叶酸-聚乙二醇-二硬脂酰磷脂酰乙醇胺 (叶酸-PEG-DSPE) 构建体掺入由二棕榈酰磷脂酰胆碱 (DPPC)、氢化大豆磷脂酰胆碱 (HSPC)、胆固醇组成的脂质双层中，制备叶酸靶向热敏脂质体 (Chol) 和磷脂酰乙醇胺在氨基位置用聚乙二醇 (PEG-PE) 以 100:50:30:6 的摩尔比衍生。在双层中掺入叶酸-PEG-PE，不会影响所得脂质体囊泡的热敏感性。 KB31细胞对叶酸-PEG-脂质体Dox的摄取比非靶向脂质体Dox高15倍。然而，在 MDR 型 KB85 的情况下，叶酸 PEG 脂质体 Dox 的摄取比非靶向脂质体 Dox 高 2 倍。细胞毒性测量表明，叶酸脂质体与热疗相结合，对于 KB31 的生长抑制作用 (IC(50)=0.16 microM) 比游离药物 (IC(50)=0.543 microM) 有效 3 倍以上。对于MDR细胞类型KB85，发现靶向脂质体联合热疗的细胞毒性比游离药物(IC(50)=1.81μM)有效4.8倍(IC(50)=0.38μM)。因此，脂质体相关的Dox可以绕过MDR细胞中的囊泡药物转运，从而增强药物的生物活性。
Conventional methods that are used to overcome multidrug resistance (MDR) often involve the coadministration of chemosensitizers and anticancer drugs. However, coadministration of many chemosensitizers with anticancer drugs, such as doxorubicin (Dox) has resulted in the exacerbation of anticancer drug toxicity. Here, we hypothesized that optimization of the anticancer drug delivery using a liposomal carrier, a suitable targeting moiety, and a physical factor such as hyperthermia offer a significant advantage in the treatment of MDR cancer cells. Since, receptors for the vitamin folic acid are frequently overexpressed on epithelial cancer cells, we used folate as our targeting moiety against two types of cell lines, the human cervical carcinoma derived KB-31 (KB31) and the resistance type KB-85 (KB85). Folate-targeted thermosensitive liposomes were prepared by incorporating 1 mol% of a folate-polyethyleneglycol-distearoylphosphatidylethanolamine (folate-PEG-DSPE) construct into a lipid bilayer composed of dipalmitoylphosphatidylcholine (DPPC), hydrogenated soy phosphatidylcholine (HSPC), cholesterol (Chol) and phosphatidylethanolamine derivatized at the amino position with polyethyleneglycol (PEG-PE) at a molar ratio of 100:50:30:6. Incorporation of folate-PEG-PE in the bilayer, did not affect the thermal sensitivity of the resultant liposome vesicles. Uptake of folate-PEG-liposomal Dox by KB31 cells was 15-fold higher than that of non-targeted liposomal Dox. However, in the case of MDR type KB85, the uptake of the folate PEG liposomal Dox was 2-fold higher than the non-targeted liposomal Dox. Cytotoxicity measurements showed that folated liposomes combined with hyperthermia were found to be over 3-fold more effective (IC(50)=0.16 microM) than the free drug (IC(50)=0.543 microM) for growth inhibition of KB31. For the MDR cell type KB85, the cytotoxicity of the targeted liposomes combined with hyperthermia were found to be 4.8 times (IC(50)=0.38 microM) more effective than the free drug (IC(50)=1.81 microM). Thus, liposome associated Dox may bypass the vesicular drug transport in MDR cells, resulting in the enhancement of the drug biological activity.