Han Zifei, Li Zihao, Raveendran Radhika, Farazi Shegufta, Cao Cheng, Chapman Robert, Stenzel Martina H
Centre for Advanced Macromolecular Design, School of Chemistry, UNSW Sydney, Kensington, NSW 2052, Australia.
School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia.
Biomacromolecules. 2023 Nov 13;24(11):5046-5057. doi: 10.1021/acs.biomac.3c00668. Epub 2023 Oct 9.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) drives apoptosis selectively in cancer cells by clustering death receptors (DR4 and DR5). While it has excellent selectivity and toxicity, the TRAIL protein has a very low circulation half-life which has hampered clinical development. Here, we developed core-cross-linked micelles that present multiple copies of a TRAIL-mimicking peptide at its surface. These micelles successfully induce apoptosis in a colon cancer cell line (COLO205) via DR4/5 clustering. Micelles with a peptide density of 15% (roughly 1 peptide/45 nm) displayed the strongest activity with an IC50 value of 0.8 μM (relative to peptide), demonstrating that the precise spatial arrangement of ligands imparted by a protein such as a TRAIL may not be necessary for DR4/5/signaling and that a statistical network of monomeric ligands may suffice. As micelles have long circulation half-lives, we propose that this could provide a potential alternative drug to TRAIL and stimulate the use of micelles in other membrane receptor clustering networks.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）通过聚集死亡受体（DR4和DR5）在癌细胞中选择性地驱动凋亡。虽然TRAIL蛋白具有出色的选择性和毒性，但其循环半衰期非常短，这阻碍了其临床开发。在此，我们开发了一种核心交联胶束，其表面呈现多个模仿TRAIL的肽拷贝。这些胶束通过DR4/5聚集成功诱导结肠癌细胞系（COLO205）凋亡。肽密度为15%（约1个肽/45nm）的胶束显示出最强活性，IC50值为0.8μM（相对于肽），这表明由TRAIL等蛋白质赋予的配体精确空间排列对于DR4/5/信号传导可能不是必需的，并且单体配体的统计网络可能就足够了。由于胶束具有较长的循环半衰期，我们认为这可以为TRAIL提供一种潜在的替代药物，并促进胶束在其他膜受体聚集网络中的应用。
