Moreira Débora A, Carvalho Eva D, Ferreira-da-Silva Frederico, Santos Sofia D, Leiro Victoria, Pêgo Ana P
i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; FEUP - Faculdade de Engenharia da Universidade do Porto, R. Dr. Roberto Frias s/n, 4200-465 Porto, Portugal.
i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.
J Control Release. 2025 Aug 10;384:113870. doi: 10.1016/j.jconrel.2025.113870. Epub 2025 May 21.
Alzheimer's disease (AD) is a severe neurological disorder and the leading cause of dementia, affecting millions globally. Dendrimers are remarkable organic macromolecules characterised by a globular, well-defined and highly branched structure featuring a high number of tuneable functional groups on their surface. Different types of dendrimers have demonstrated antioxidant, anti-inflammatory, and anti-amyloidogenic properties, showing their potential as powerful nanodrugs in AD. However, none of these dendrimers exhibit biodegradability under physiological conditions. This study explored the therapeutic potential of biodegradable PEG-GATGE (Poly(Ethylene Glycol)-Gallic Acid-Triethylene Glycol Ester) block copolymers against the Amyloid β (Aβ) (1-42) peptide, a key player in AD pathology. We focused on two dendritic structures: one functionalised with positively charged benzylamine terminal groups (fbB) and another functionalised with negatively charged benzoic acid terminal groups (fbBz). Our research aimed to evaluate their ability to inhibit Aβ (1-42) fibrillation by examining aggregation kinetics, secondary structure, and aggregate morphology. Additionally, we assessed their interactions with preformed Aβ species and neuroprotective effects in hippocampal neuron cultures. Results showed that both dendrimers modulate Aβ fibrillation in a peptide/dendrimer ratio-dependent manner and can also interact with preformed Aβ fibrils. Notably, only the positively charged dendrimer, fbB, effectively prevented the toxic association of Aβ oligomers with neurons. These findings emphasise the substantial promise of this family of biodegradable dendrimers as innovative nanodrugs in the fight against AD, paving the way for novel therapeutic strategies in neurodegenerative disorders.
阿尔茨海默病（AD）是一种严重的神经疾病，也是痴呆症的主要病因，全球数百万人受其影响。树枝状大分子是一类引人注目的有机大分子，其特征在于具有球形、结构明确且高度分支的结构，表面有大量可调节的官能团。不同类型的树枝状大分子已显示出抗氧化、抗炎和抗淀粉样蛋白生成特性，表明它们作为AD中强大的纳米药物具有潜力。然而，这些树枝状大分子在生理条件下均不具有生物降解性。本研究探索了可生物降解的聚乙二醇-没食子酸-三甘醇酯（PEG-GATGE）嵌段共聚物针对淀粉样β（Aβ）（1-42）肽的治疗潜力，Aβ（1-42）肽是AD病理过程中的关键因素。我们重点研究了两种树枝状结构：一种用带正电荷的苄胺端基官能化（fbB），另一种用带负电荷的苯甲酸端基官能化（fbBz）。我们的研究旨在通过研究聚集动力学、二级结构和聚集体形态来评估它们抑制Aβ（1-42）纤维化的能力。此外，我们评估了它们与预先形成的Aβ物种的相互作用以及在海马神经元培养物中的神经保护作用。结果表明，两种树枝状大分子均以肽/树枝状大分子比例依赖的方式调节Aβ纤维化，并且还可以与预先形成的Aβ纤维相互作用。值得注意的是，只有带正电荷的树枝状大分子fbB有效地阻止了Aβ寡聚体与神经元的毒性结合。这些发现强调了这一类可生物降解树枝状大分子作为对抗AD的创新纳米药物的巨大前景，为神经退行性疾病的新型治疗策略铺平了道路。
