Department of Biochemical Engineering, School of Chemical Engineering and Technology and Key Laboratory of Systems Bioengineering and Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin 300350, China.
Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
Langmuir. 2023 Sep 12;39(36):12576-12589. doi: 10.1021/acs.langmuir.3c01169. Epub 2023 Aug 25.
Alzheimer's disease (AD) remains incurable due to its complex pathogenesis. The deposition of β-amyloid (Aβ) in the brain appears much earlier than any clinical symptoms and plays an essential role in the occurrence and development of AD neuropathology, which implies the importance of early theranostics. Herein, we designed a self-assembled bifunctional nanoparticle (LC8-pCG-fLC8) for Aβ fluorescent diagnosis and inhibition. The nanoparticle was synthesized by click chemistry from Aβ-targeting peptide Ac-LVFFARKC-NH (LC8) and an Aβ fluorescent probe f with the zwitterionic copolymer poly(carboxybetaine methacrylate-glycidyl methacrylate) (p(CBMA-GMA), pCG). Owing to the high reactivity of epoxy groups, the peptide concentration of LC8-pCG-fLC8 nanoparticles reached about 4 times higher than that of the existing inhibitor LVFFARK@poly(carboxybetaine) (LK7@pCB). LC8-pCG-fLC8 exhibited remarkable inhibitory capability (suppression efficiency of 83.0% at 20 μM), altered the aggregation pathway of Aβ, and increased the survival rate of amyloid-induced cultured cells from 76.5% to 98.0% at 20 μM. Notably, LC8-pCG-fLC8 possessed excellent binding affinity, good biostability, and high fluorescence responsivity to β-sheet-rich Aβ oligomers and fibrils, which could be used for the early diagnosis of Aβ aggregation. More importantly, tests using transgenic CL2006 stain showed that LC8-pCG-fLC8 could specifically image Aβ plaques, prolong the lifespan (from 13 to 17 days), and attenuate the AD-like symptoms (reducing paralysis and Aβ deposition). Therefore, self-assembled nanoparticles hold great potential in AD theranostics.
阿尔茨海默病（AD）由于其复杂的发病机制仍然无法治愈。β-淀粉样蛋白（Aβ）在大脑中的沉积比任何临床症状都早得多，在 AD 神经病理学的发生和发展中起着至关重要的作用，这意味着早期治疗的重要性。在这里，我们设计了一种自组装的双功能纳米颗粒（LC8-pCG-fLC8）用于 Aβ 的荧光诊断和抑制。该纳米颗粒通过点击化学由靶向 Aβ 的肽 Ac-LVFFARKC-NH（LC8）和 Aβ 荧光探针 f 与两性离子共聚物聚（羧基甜菜碱甲基丙烯酸酯-甲基丙烯酸缩水甘油酯）（p(CBMA-GMA)，pCG）合成。由于环氧基团的高反应性，LC8-pCG-fLC8 纳米颗粒的肽浓度比现有的抑制剂 LVFFARK@poly(carboxybetaine)（LK7@pCB）高约 4 倍。LC8-pCG-fLC8 表现出显著的抑制能力（在 20 μM 时抑制效率为 83.0%），改变了 Aβ 的聚集途径，并将淀粉样蛋白诱导的培养细胞的存活率从 76.5%提高到 20 μM 时的 98.0%。值得注意的是，LC8-pCG-fLC8 具有良好的结合亲和力、良好的生物稳定性和对富含β-折叠的 Aβ 寡聚体和纤维的高荧光响应性，可用于 Aβ 聚集的早期诊断。更重要的是，使用转染 CL2006 品系的测试表明，LC8-pCG-fLC8 可以特异性地对 Aβ 斑块进行成像，延长寿命（从 13 天延长到 17 天），并减轻 AD 样症状（减少瘫痪和 Aβ 沉积）。因此，自组装纳米颗粒在 AD 的治疗中有很大的潜力。
