Lee Ashlynn L Z, Wang Yong, Cheng Han Yin, Pervaiz Shazib, Yang Yi Yan
Institute of Bioengineering and Nanotechnology, Drugs, Proteins and Genes Delivery, 31 Biopolis Way, Singapore 138669, Singapore.
Biomaterials. 2009 Feb;30(5):919-27. doi: 10.1016/j.biomaterials.2008.10.062. Epub 2008 Nov 29.
We have recently reported micellar nanoparticles self-assembled from a biodegradable and amphiphilic copolymer poly{(N-methyldietheneamine sebacate)-co-[(cholesteryl oxocarbonylamido ethyl) methyl bis(ethylene) ammonium bromide] sebacate}, P(MDS-co-CES), which were able to deliver small molecular drugs and biomacromolecules such as genes and functional proteins individually or simultaneously into various types of cells. In this study, these cationic micellar nanoparticles were employed as carriers to co-deliver paclitaxel and Herceptin for achieving targeted delivery of paclitaxel to human epidermal growth factor receptor-2 (HER2/neu)-overexpressing human breast cancer cells, and enhanced cytotoxicity through synergistic activities. Paclitaxel-loaded nanoparticles have an average size less than 120 nm and a zeta potential of about 60 mV. Herceptin was complexed onto the surface of the nanoparticles. The drug-loaded nanoparticle/Herceptin complexes remained stable under physiologically-simulating conditions with sizes at around 200 nm. The nanoparticles delivered Herceptin much more efficiently than BioPorter, a commercially available lipid-based protein carrier, and displayed a much higher anti-cancer effectiveness. Twice-repeated daily treatment with Herceptin showed significantly higher cytotoxicity especially in HER2-overexpressing breast cancer cells when compared to single treatment. Anti-cancer effects of this co-delivery system was investigated in human breast cancer cell lines with varying degrees of HER2 expression level, namely, MCF7, T47D and BT474. The co-delivery of Herceptin increased the cytotoxicity of paclitaxel and this enhancement showed a dependency on their HER2 expression levels. Targeting ability of this co-delivery system was demonstrated through confocal images, which showed significantly higher cellular uptake in HER2-overexpressing BT474 cells as compared to HER2-negative HEK293 cells. This co-delivery system may have important clinical implications against HER2-overexpressing breast cancers.
我们最近报道了由可生物降解的两亲共聚物聚{（N-甲基二乙烯胺癸二酸酯）-共-[（胆固醇氧羰基酰胺基乙基）甲基双（乙烯）溴化铵]癸二酸酯}，即P（MDS-co-CES）自组装而成的胶束纳米颗粒，其能够将小分子药物和生物大分子（如基因和功能蛋白）单独或同时递送至各种类型的细胞中。在本研究中，这些阳离子胶束纳米颗粒被用作载体，用于共同递送紫杉醇和赫赛汀，以实现将紫杉醇靶向递送至人表皮生长因子受体2（HER2/neu）过表达的人乳腺癌细胞，并通过协同作用增强细胞毒性。负载紫杉醇的纳米颗粒平均尺寸小于120nm，zeta电位约为60mV。赫赛汀被复合到纳米颗粒表面。载药纳米颗粒/赫赛汀复合物在生理模拟条件下保持稳定，尺寸约为200nm。与市售的基于脂质的蛋白载体BioPorter相比，纳米颗粒递送赫赛汀的效率更高，并且显示出更高的抗癌效果。与单次治疗相比，每天重复两次使用赫赛汀治疗显示出显著更高的细胞毒性，尤其是在HER2过表达的乳腺癌细胞中。在具有不同程度HER2表达水平的人乳腺癌细胞系，即MCF7、T47D和BT474中研究了这种共同递送系统的抗癌效果。赫赛汀的共同递送增加了紫杉醇的细胞毒性，并且这种增强表现出对它们HER2表达水平的依赖性。通过共聚焦图像证明了这种共同递送系统的靶向能力，与HER2阴性的HEK293细胞相比，该图像显示HER2过表达的BT474细胞中的细胞摄取明显更高。这种共同递送系统可能对HER2过表达的乳腺癌具有重要的临床意义。
