Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.
Drug Deliv. 2012 Nov;19(8):363-70. doi: 10.3109/10717544.2012.724473. Epub 2012 Oct 3.
Overexpression of drug efflux pump P-gp is one of the major reasons to cause multidrug resistance (MDR). To overcome P-gp mediated MDR, modulators, so called P-gp inhibitors, can be used to block efflux pump activity. Elacridar is one of the most potent P-gp inhibitors, which can cause irreversible and total P-gp blockage. Elacridar, among with other P-gp inhibitors, can be used in combination with anticancer drugs to enhance the effectiveness of chemotherapy against resistant tumor cells. On the other hand, P-gp is presented in normal tissues, thus non-selective blockage of P-gp can cause undesired side effects. Therefore, it is important to deliver P-gp inhibitor only to the tumor cells (along with anticancer drug) and limit its distribution in the body. In this study, we have developed PEG-PE-based long-circulating ca. 15 nm micelles co-loaded with elacridar and paclitaxel, and investigated their ability to overcome paclitaxel resistance in two cancer cell lines. Vitamin E, a common solubility enhancer for PEG-PE micelles, was found to have a negative effect on both particle size and encapsulation efficiencies. The human MDR1 gene-transfected and thus paclitaxel-resistant MDCKII-MDR1 P-gp overexpressing cells were used for cytotoxicity evaluation. Even though PEG-PE based micelles itself have a potential to enhance the cytotoxicity of paclitaxel, elacridar/paclitaxel-co-loaded micelles demonstrated the highest cytotoxicity compared to both free and micellar paclitaxel. The obtained results suggest that co-loading of paclitaxel and elacridar into micellar drug carriers results in promising preparations capable of overcoming paclitaxel resistance.
药物外排泵 P-糖蛋白（P-gp）的过度表达是导致多药耐药（MDR）的主要原因之一。为了克服 P-gp 介导的 MDR，可以使用调节剂，即所谓的 P-gp 抑制剂，来阻断外排泵的活性。依利格鲁司他（Elacridar）是最有效的 P-gp 抑制剂之一，它可以导致 P-gp 的不可逆和完全阻断。依利格鲁司他与其他 P-gp 抑制剂一起，可以与抗癌药物联合使用，以增强化疗对耐药肿瘤细胞的效果。另一方面，P-gp 存在于正常组织中，因此非选择性阻断 P-gp 可能会引起不必要的副作用。因此，将 P-gp 抑制剂递送到肿瘤细胞（与抗癌药物一起）并限制其在体内的分布非常重要。在这项研究中，我们开发了基于 PEG-PE 的长循环 ca.15nm 胶束，共载有依利格鲁司他和紫杉醇，并研究了它们在两种癌细胞系中克服紫杉醇耐药的能力。维生素 E 是 PEG-PE 胶束的常见增溶剂，但它对粒径和包封效率都有负面影响。我们使用人 MDR1 基因转染的、因此紫杉醇耐药的 MDCKII-MDR1 P-gp 过表达细胞进行细胞毒性评估。尽管基于 PEG-PE 的胶束本身具有增强紫杉醇细胞毒性的潜力，但与游离紫杉醇和胶束紫杉醇相比，依利格鲁司他/紫杉醇共载胶束显示出最高的细胞毒性。研究结果表明，将紫杉醇和依利格鲁司他共载到胶束药物载体中可以得到有前途的制剂，能够克服紫杉醇耐药性。
