School of Chemical Engineering, The University of Adelaide, Adelaide, SA 5005, Australia.
Pharmacol Res. 2011 Jan;63(1):51-8. doi: 10.1016/j.phrs.2010.10.012. Epub 2010 Oct 28.
Folic acid-conjugated albumin nanospheres (FA-AN) have been developed to provide an actively targetable drug delivery system for improved drug targeting of cancer cells with reduced side effects. The nanospheres were prepared by conjugating folic acid onto the surface of albumin nanospheres using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC) as a catalyst. To test the efficacy of these nanospheres as a potential delivery platform, doxorubicin-loaded albumin nanospheres (DOX-AN) and doxorubicin-loaded FA-AN (FA-DOX-AN) were prepared by entrapping DOX (an anthracycline, antibiotic drug widely used in cancer chemotherapy that works by intercalating DNA) into AN and FA-AN nanoparticles. Cell uptake of the DOX was then measured. The results show that FA-AN was incorporated into HeLa cells (tumor cells) only after 2.0h incubation, whereas HeLa cells failed to incorporate albumin nanospheres without conjugated folic acid after 4.0h incubation. When HeLa cells were treated with the DOX-AN, FA-DOX-AN nanoparticles or free DOX, cell viability decreased with increasing culture time (i.e. cell death increases with time) over a 70h period. Cell viability was always the lowest for free DOX followed by FA-DOX-AN4 and then DOX-AN. In a second set of experiments, HeLa cells washed to remove excess DOX after an initial incubation for 2h were incubated for 70h. The corresponding cell viability was slightly higher when the cells were treated with FA-DOX-AN or free DOX whilst cells treated with DOX-AN nanoparticles remained viable. The above experiments were repeated for non-cancerous, aortic smooth muscle cells (AoSMC). As expected, cell viability of the HeLa cells (with FA receptor alpha, FRα) and AoSMC cells (without FRα) decreased rapidly with time in the presence of free DOX, but treatment with FA-DOX-AN resulted in selective killing of the tumor cells. These results indicated that FA-AN may be used as a promising actively targetable drug delivery system to improve drug targeting to cancer cells.
叶酸偶联白蛋白纳米球（FA-AN）已被开发用于提供主动靶向药物递送系统，以改善对癌细胞的药物靶向作用，并减少副作用。通过使用 1-乙基-3-（3-二甲基氨基丙基）碳二亚胺（EDAC）作为催化剂将叶酸偶联到白蛋白纳米球的表面上来制备纳米球。为了测试这些纳米球作为潜在递送平台的功效，通过将阿霉素（一种蒽环类抗生素药物，广泛用于癌症化疗，通过嵌入 DNA 起作用）包埋到 AN 和 FA-AN 纳米球中制备了载阿霉素的白蛋白纳米球（DOX-AN）和载阿霉素的 FA-AN（FA-DOX-AN）。然后测量 DOX 的细胞摄取。结果表明，FA-AN 在孵育 2.0 小时后仅被 HeLa 细胞（肿瘤细胞）摄取，而没有偶联叶酸的白蛋白纳米球在孵育 4.0 小时后 HeLa 细胞未能摄取。当用 DOX-AN、FA-DOX-AN 纳米颗粒或游离 DOX 处理 HeLa 细胞时，随着培养时间的延长（即随着时间的推移细胞死亡增加），70 小时内细胞活力降低。细胞活力始终最低，游离 DOX 之后是 FA-DOX-AN4，然后是 DOX-AN。在第二组实验中，在用 DOX 孵育 2 小时后，用 DOX 处理的 HeLa 细胞被洗去多余的 DOX 并孵育 70 小时。在用 FA-DOX-AN 或游离 DOX 处理的细胞中，相应的细胞活力略高，而在用 DOX-AN 纳米颗粒处理的细胞中保持存活。对非癌细胞，主动脉平滑肌细胞（AoSMC）重复了上述实验。正如预期的那样，HeLa 细胞（具有 FA 受体α，FRα）和 AoSMC 细胞（没有 FRα）在游离 DOX 存在下的细胞活力随时间迅速下降，但是用 FA-DOX-AN 处理导致肿瘤细胞的选择性杀伤。这些结果表明，FA-AN 可用作有前途的主动靶向药物递送系统，以改善对癌细胞的药物靶向作用。
