Department of Chemical & Biomolecular Engineering, National University of Singapore, Block E5, 02-11, 4 Engineering Drive 4, Singapore 117576, Singapore.
Biomaterials. 2013 Dec;34(38):10160-71. doi: 10.1016/j.biomaterials.2013.09.043. Epub 2013 Oct 3.
We developed a system of Cetuximab-conjugated micelles of vitamin E TPGS for targeted delivery of docetaxel as a model anticancer drug for treatment of the triple negative breast cancer (TNBC), which shows no expression of either one of the hormone progesterone receptor (PR), estrogen receptor (ER) and epidermal growth factor receptor 2 (HER2) and is thus more difficult to be treated than the positive breast cancer. Such micelles are of desired particle size, drug loading, drug encapsulation efficiency and drug release profile. Their surface morphology, surface charge and surface chemistry were also characterized. The fibroblast cells (NIH3T3), HER2 overexpressed breast cancer cells (SK-BR-3), ER and PR overexpressed breast cancer cells (MCF7), and TNBC cells of high, moderate and low EGFR expression (MDA MB 468, MDA MB 231 and HCC38) were employed to access in vitro cellular uptake of the coumarin 6 loaded TPGS micelles and cytotoxicity of docetaxel formulated in the micelles. The high IC50 value, which is the drug concentration needed to kill 50% of the cells in a designated period such as 24 h, obtained from Taxotere(®) showed that the TNBC cells are indeed more resistant to the free drug than the positive breast cancer cells. However, the therapeutic effects of docetaxel could be greatly enhanced by the formulation of Cetuximab conjugated TPGS micelles, which demonstrated 205.6 and 223.8 fold higher efficiency than Taxotere(®) for the MDA MB 468 and MDA MB 231 cell lines respectively.
我们开发了一种 EGFR 靶向的载多西紫杉醇维生素 E TPGS 胶束给药系统,用于治疗三阴性乳腺癌(TNBC)。TNBC 既不表达孕激素受体(PR)、雌激素受体(ER)也不表达表皮生长因子受体 2(HER2),因此比阳性乳腺癌更难治疗。这种胶束具有理想的粒径、载药量、包封率和药物释放特性。我们还对其表面形态、表面电荷和表面化学性质进行了表征。我们使用成纤维细胞(NIH3T3)、过表达 HER2 的乳腺癌细胞(SK-BR-3)、过表达 ER 和 PR 的乳腺癌细胞(MCF7)以及高、中、低 EGFR 表达的 TNBC 细胞(MDA MB 468、MDA MB 231 和 HCC38),研究了载香豆素 6 的 TPGS 胶束的细胞摄取以及包载在胶束中的多西紫杉醇的细胞毒性。Taxotere(®)的 IC50 值(杀死指定时间如 24 小时内 50%的细胞所需的药物浓度)较高,这表明 TNBC 细胞对游离药物的耐药性确实高于阳性乳腺癌细胞。然而,通过将多西紫杉醇制成 EGFR 靶向的 TPGS 胶束,其治疗效果得到了极大的增强,对 MDA MB 468 和 MDA MB 231 细胞系的效率分别比 Taxotere(®)高 205.6 倍和 223.8 倍。