Department of Chemistry, Bar-Ilan Institute of Nanotechnology and Advanced Materials, Ramat-Gan 52900, Israel.
Biomacromolecules. 2012 Sep 10;13(9):2662-70. doi: 10.1021/bm3011177. Epub 2012 Aug 28.
Protein aggregation into amyloid fibrils is implicated in the pathogenesis of many neurodegenerative diseases. Engineered nanoparticles have emerged as a potential approach to alter the kinetics of protein fibrillation process. Yet, there are only a few reports describing the use of nanoparticles for inhibition of amyloid-β 40 (Aβ(40)) peptide aggregation, involved in Alzheimer's disease (AD). In the present study, we designed new uniform biocompatible amino-acid-based polymer nanoparticles containing hydrophobic dipeptides in the polymer side chains. The dipeptide residues were designed similarly to the hydrophobic core sequence of Aβ. Poly(N-acryloyl-L-phenylalanyl-L-phenylalanine methyl ester) (polyA-FF-ME) nanoparticles of 57 ± 6 nm were synthesized by dispersion polymerization of the monomer A-FF-ME in 2-methoxy ethanol, followed by precipitation of the obtained polymer in aqueous solution. Cell viability assay confirmed that no significant cytotoxic effect of the polyA-FF-ME nanoparticles on different human cell lines, e.g., PC-12 and SH-SY5Y, was observed. A significantly slow secondary structure transition from random coil to β-sheets during Aβ(40) fibril formation was observed in the presence of these nanoparticles, resulting in significant inhibition of Aβ(40) fibrillation kinetics. However, the polyA-FF-ME analogous nanoparticles containing the L-alanyl-L-alanine (AA) dipeptide in the polymer side groups, polyA-AA-ME nanoparticles, accelerate the Aβ(40) fibrillation kinetics. The polyA-FF-ME nanoparticles and the polyA-AA-ME nanoparticles may therefore contribute to a mechanistic understanding of the fibrillation process, leading to the development of therapeutic strategies against amyloid-related diseases.
蛋白质聚集成淀粉样纤维与许多神经退行性疾病的发病机制有关。工程纳米颗粒已成为改变蛋白质纤维形成过程动力学的一种潜在方法。然而，只有少数报道描述了使用纳米颗粒抑制与阿尔茨海默病（AD）相关的淀粉样β 40（Aβ（40））肽聚集。在本研究中，我们设计了新的均匀生物相容性氨基酸基聚合物纳米颗粒，其聚合物侧链中含有疏水性二肽。二肽残基的设计类似于 Aβ 的疏水性核心序列。通过单体 A-FF-ME 在 2-甲氧基乙醇中的分散聚合合成了 57±6nm 的聚（N-丙烯酰基-L-苯丙氨酸-L-苯丙氨酸甲酯）（polyA-FF-ME）纳米颗粒，然后将得到的聚合物在水溶液中沉淀。细胞活力测定证实，polyA-FF-ME 纳米颗粒对不同的人类细胞系（例如 PC-12 和 SH-SY5Y）没有明显的细胞毒性作用。在这些纳米颗粒存在下，观察到 Aβ（40）纤维形成过程中从无规卷曲到β-折叠的二级结构转变明显减慢，导致 Aβ（40）纤维形成动力学显著抑制。然而，在聚合物侧基中含有 L-丙氨酸-L-丙氨酸（AA）二肽的类似 polyA-FF-ME 的纳米颗粒，即 polyA-AA-ME 纳米颗粒，加速了 Aβ（40）纤维形成动力学。polyA-FF-ME 纳米颗粒和 polyA-AA-ME 纳米颗粒因此可能有助于深入了解纤维形成过程，并为针对淀粉样相关疾病的治疗策略的发展做出贡献。
