Pharmaceutical Technology Department, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey.
Drug Deliv. 2012 May;19(4):169-76. doi: 10.3109/10717544.2012.674163. Epub 2012 Apr 16.
The over-expression of the P-glycoprotein (P-gp) in cancer cells is one of the main reasons of the acquired Multidrug Resistance (MDR). Combined treatment of MDR cancer cells with P-gp inhibitors and chemotherapeutic agents could result in reversal of resistance in P-gp-expressing cells. In this study, paclitaxel (PTX) was co-encapsulated in actively targeted (anticancer mAb 2C5-modified) polymeric lipid-core PEG-PE-based micelles with Cyclosporine A (CycA), which is one of the most effective first generation P-gp inhibitors. Cell culture studies performed using MDCKII (parental and MDR1) cell lines to investigate the potential MDR reversal effect of the formulations. The average size of both empty and loaded PEG₂₀₀₀-PE/Vitamin E mixed micelles was found between 10 and 25 nm. Zeta potentials of the formulations were found between -7 and -35 mV. The percentage of PTX in the micelles was found higher than 3% for both formulations and cumulative PTX release of about 70% was demonstrated. P-gp inhibition with CycA caused an increase in the cytotoxicity of PTX. Dual-loaded micelles demonstrated significantly higher cytotoxicity in the resistant MDCKII-MDR1 cells than micelles loaded with PTX alone. Micelle modification with mAb 2C5 results in the highest cytotoxicity against resistant cells, with or without P-gp modulator, probably because of better internalization bypassing the P-gp mechanism. Our results suggest that micelles delivering a combination of P-gp modulator and anticancer drug or micelles loaded with only PTX, but targeted with mAb 2C5 represent a promising approach to overcome drug resistance in cancer cells.
多药耐药（MDR）的主要原因之一是癌细胞中 P-糖蛋白（P-gp）的过度表达。用 P-gp 抑制剂和化疗药物联合治疗 MDR 癌细胞可导致 P-gp 表达细胞的耐药性逆转。在这项研究中，紫杉醇（PTX）与环孢素 A（CycA）共包封在主动靶向（抗癌单克隆抗体 2C5 修饰）聚合物脂质核 PEG-PE 基胶束中，CycA 是最有效的第一代 P-gp 抑制剂之一。使用 MDCKII（亲本和 MDR1）细胞系进行细胞培养研究，以研究制剂的潜在 MDR 逆转作用。空和负载 PEG₂₀₀₀-PE/Vitamin E 混合胶束的平均粒径在 10 到 25nm 之间。制剂的 Zeta 电位在-7 到-35mV 之间。两种制剂中 PTX 在胶束中的百分比均高于 3%，并证明了约 70%的 PTX 累积释放。CycA 对 P-gp 的抑制作用导致 PTX 的细胞毒性增加。与单独负载 PTX 的胶束相比，双重负载的胶束在耐药 MDCKII-MDR1 细胞中显示出显著更高的细胞毒性。用 mAb 2C5 修饰胶束导致对耐药细胞具有最高的细胞毒性，无论是否存在 P-gp 调节剂，这可能是因为更好地内化绕过了 P-gp 机制。我们的结果表明，递送 P-gp 调节剂和抗癌药物的组合的胶束或仅负载 PTX 但靶向 mAb 2C5 的胶束代表了克服癌细胞耐药性的一种有前途的方法。
