Polymeric Nanodiscs Comprising 5-Fluorouracil for Inhibition of Protein Aggregation and Their Anti-Alzheimer's Activity in the Drosophila Model.

IF 4.1 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Chemical Neuroscience Pub Date : 2025-02-05 Epub Date: 2024-12-18 DOI:10.1021/acschemneuro.4c00458

Pranita Rananaware, Seekha Naik, Lokanath Mishra, Rangappa S Keri, Monalisa Mishra, Varsha P Brahmkhatri

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Abstract

Nanoconjugates are promising for therapeutic drug delivery and targeted applications due to the numerous opportunities to functionalize their surface. The present study reports the synthesis of 5-fluorouracil (5-FU)-entrapped polyvinylpyrrolidone (PVP) nanoconjugates, precisely 5-FU-PVP and 5-FU-PVP-Au, and the evaluation of protein aggregation inhibition efficiency. The 5-FU-loaded polymer nanoconjugates were functionalized with gold nanoparticles and analyzed using characterization techniques like dynamic light scattering, UV-visible spectroscopy, Fourier-transform infrared spectroscopy, and zeta potential analysis. These conjugates exhibit consistent morphology with a spherical, flat, disc-like structure. The 5-FU-PVP and 5-FU-PVP-Au nanoconjugates exhibited a high drug loading, up to 81% and 90%, respectively. The nanoconjugates exhibited prolonged drug delivery of 5-FU from 5-FU-PVP and 5-FU-PVP-Au, wherein 5-FU-PVP-Au depicted a higher drug release. They were investigated for inhibiting the protein hen egg white lysozyme (HEWL) aggregation by ThT fibril size measurement, binding assay, and electron microscopy, and the results showed that conjugates repressed the fibrillogenesis in HEWL. The prominent activity of amyloid aggregation inhibition for HEWL using 5-FU-PVP and 5-FU-PVP-Au was found to be 29 μg.mL^-1 and 27 μg.mL^-1, respectively. The dissociation of amyloid aggregates was achieved against 5-FU-PVP and 5-FU-PVP-Au at 27 μg.mL^-1 and 25 μg.mL^-1, respectively. Furthermore, the nanoconjugates were investigated for anti-Alzheimer's activity in the Drosophila model. A Drosophila model of Alzheimer's disease (AD) was developed that expressed Aβ42 peptides in the neuronal secretory system to comprehend the pathogenic effects of Aβ42 in vivo. All the results demonstrate that polymer nanoconjugates exhibit more effective inhibition of protein aggregation than bare drugs.

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含有5-氟尿嘧啶的聚合物纳米片抑制蛋白质聚集及其在果蝇模型中的抗阿尔茨海默病活性。

纳米缀合物在治疗药物传递和靶向应用方面很有前景，因为它们有许多机会使其表面功能化。本研究报道了5-氟尿嘧啶（5-FU）包埋聚乙烯吡咯烷酮（PVP）纳米偶联物的合成，即5-FU-PVP和5-FU-PVP- au，并对其蛋白聚集抑制效率进行了评价。将负载5- fu的聚合物纳米缀合物用金纳米粒子功能化，并使用动态光散射、紫外可见光谱、傅里叶变换红外光谱和zeta电位分析等表征技术进行分析。这些共轭物具有一致的球形、扁平、圆盘状结构。5-FU-PVP和5-FU-PVP- au纳米偶联物的载药量分别高达81%和90%。纳米偶联物表现出5-FU从5-FU- pvp和5-FU- pvp - au中释放药物的时间延长，其中5-FU- pvp - au表现出更高的药物释放。通过ThT纤维大小测定、结合实验和电镜观察，研究了它们对蛋白蛋清溶菌酶（HEWL）聚集的抑制作用，结果表明，偶联物抑制了HEWL的纤维形成。5-FU-PVP和5-FU-PVP- au对HEWL的淀粉样蛋白聚集抑制活性显著，均为29 μg。mL-1和27 μg。分别mL-1。5-FU-PVP和5-FU-PVP- au在27 μg时实现了淀粉样蛋白聚集体的解离。mL-1和25 μg。分别mL-1。此外，研究了纳米偶联物在果蝇模型中的抗阿尔茨海默病活性。为了了解Aβ42在体内的致病作用，建立了在神经元分泌系统中表达Aβ42肽的果蝇阿尔茨海默病（AD）模型。这些结果表明，聚合物纳米缀合物对蛋白质聚集的抑制作用比单纯的药物更有效。

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来源期刊

ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL

CiteScore

9.20

自引率

4.00%

发文量

323

审稿时长

1 months

期刊介绍： ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research

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Issue Publication Information Issue Editorial Masthead Polymeric Nanodiscs Comprising 5-Fluorouracil for Inhibition of Protein Aggregation and Their Anti-Alzheimer's Activity in the Drosophila Model. Application and Mechanism of Action of a Ketogenic Diet in Antiepileptic Therapy. Biological Amyloids Chemically Damage DNA.