Habitat Centre , Institute of Nano Science and Technology , Phase-10 , Mohali 160062 , Punjab , India.
ACS Appl Mater Interfaces. 2020 Feb 5;12(5):5658-5670. doi: 10.1021/acsami.9b22214. Epub 2020 Jan 27.
Alzheimer's disease (AD) is one of the common causes of dementia and mild cognitive impairments, which is progressively expanding among the elderly population worldwide. A short Amyloid-β (Aβ) peptide generated after amyloidogenic processing of amyloid precursor protein exist as intermolecular β-sheet rich oligomeric, protofibriler, and fibrillar structures and believe to be toxic species which instigate neuronal pathobiology in the brain and deposits as senile plaque. Enormous efforts are being made to develop an effective anti-AD therapy that can target Aβ processing, aggregation, and propagation and provide a synergistic neuroprotective effect. However, a nanodrug prepared from natural origin can confer a multimodal synergistic chemo/photothermal inhibition of Aβ pathobiology is not yet demonstrated. In the present work, we report a dopamine-melatonin nanocomposite (DM-NC), which possesses a synergistic near-infrared (NIR) responsive photothermal and pharmacological modality. The noncovalent interaction-mediated self-assembly of melatonin and dopamine oxidative intermediates leads to the evolution of DM-NCs that can withstand variable pH and peroxide environment. NIR-activated melatonin release and photothermal effect collectively inhibit Aβ nucleation, self-seeding, and propagation and can also disrupt the preformed Aβ fibers examined using in vitro Aβ aggregation and Aβ-misfolding cyclic amplification assays. The DM-NCs display a higher biocompatibility to neuroblastoma cells, suppress the AD-associated generation of intracellular reactive oxygen species, and are devoid of any negative impact on the axonal growth process. In okadaic acid-induced neuroblastoma and ex vivo midbrain slice culture-based AD model, DM-NCs exposure suppresses the intracellular Aβ production, aggregation, and accumulation. Therefore, this nature-derived nanocomposite demonstrates a multimodal NIR-responsive synergistic photothermal and pharmacological modality for effective AD therapy.
阿尔茨海默病（AD）是痴呆症和轻度认知障碍的常见病因之一，在全球老年人群中呈逐渐扩大趋势。淀粉样前体蛋白经淀粉样蛋白生成处理后产生的短淀粉样蛋白β（Aβ）肽以分子间富含β-片层的寡聚体、原纤维和纤维结构存在，被认为是具有毒性的物质，会引发大脑中的神经元病理生物学变化，并沉积为老年斑。目前正在进行大量努力来开发有效的抗 AD 治疗方法，该方法可以靶向 Aβ 处理、聚集和传播，并提供协同的神经保护作用。然而，尚未证明源自天然来源的纳米药物可以发挥协同的化学/光热抑制 Aβ 病理生物学作用。在本工作中，我们报告了一种多巴胺-褪黑素纳米复合材料（DM-NC），它具有协同的近红外（NIR）响应光热和药理模式。褪黑素和多巴胺氧化中间体的非共价相互作用介导的自组装导致 DM-NC 的演变，使其能够耐受不同的 pH 值和过氧化物环境。NIR 激活的褪黑素释放和光热效应共同抑制 Aβ成核、自我播种和传播，并且还可以使用体外 Aβ 聚集和 Aβ 错误折叠循环扩增测定来破坏预先形成的 Aβ 纤维。DM-NC 对神经母细胞瘤具有更高的生物相容性，可抑制 AD 相关的细胞内活性氧的产生，并且对轴突生长过程没有任何负面影响。在冈田酸诱导的神经母细胞瘤和基于体外脑片培养的 AD 模型中，DM-NC 暴露可抑制细胞内 Aβ 的产生、聚集和积累。因此，这种源自天然的纳米复合材料为有效的 AD 治疗展示了一种多模态近红外响应协同光热和药理模式。
