Myc Andrzej, Patri Anil K, Baker James R
Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, BSRB, Ann Arbor, MI 48109-0648, USA.
Biomacromolecules. 2007 Oct;8(10):2986-9. doi: 10.1021/bm700727g. Epub 2007 Sep 18.
Our previous studies have demonstrated the efficacy of generation 5 poly(amidoamine) dendrimers (G5-PAMAM) as a platform for the targeted delivery of chemotherapeutics. However, anticancer therapy can be subverted by anti-apoptotic changes in cancer cells. Bcl-2 and several of its peptides are commonly overexpressed in a number of cancers. A means to reverse this anti-apoptotic mechanism is to expose the cells to BH3 peptide, which has a homology to the anti-apoptotic Bcl-2 protein. This cannot be done indiscriminately because it can induce apoptosis in normal cells. In order to specifically target BH3 peptides to cancer cells, we synthesized a trifunctional, G5-PAMAM-based nanodevice to which folic acid was conjugated as a targeting agent, along with fluorescein isothiocyanate as the reporter agent and BH3 peptides that were used to induce apoptosis. The results show, for the first time, the therapeutic potential of targeted BH3 peptides as a means of inducing apoptosis by interfering with anti-apoptotic proteins within specific cells.
我们之前的研究已经证明了第5代聚（酰胺胺）树枝状大分子（G5-PAMAM）作为化疗药物靶向递送平台的有效性。然而，抗癌治疗可能会因癌细胞中的抗凋亡变化而受到干扰。Bcl-2及其几种肽在许多癌症中通常过度表达。逆转这种抗凋亡机制的一种方法是使细胞暴露于BH3肽，其与抗凋亡Bcl-2蛋白具有同源性。但不能随意这样做，因为它会诱导正常细胞凋亡。为了将BH3肽特异性靶向癌细胞，我们合成了一种基于G5-PAMAM的三功能纳米装置，其上缀合了叶酸作为靶向剂，同时还有异硫氰酸荧光素作为报告剂以及用于诱导凋亡的BH3肽。结果首次表明，靶向BH3肽作为通过干扰特定细胞内抗凋亡蛋白来诱导凋亡的一种手段具有治疗潜力。
