Gomes-da-Silva Natália Cristina, Xavier-de-Britto Isabelle, Soares Marilia Amável Gomes, Yoshihara Natalia Mayumi Andrade, Ilem Özdemir Derya, Ricci-Junior Eduardo, Fechine Pierre Basílio Almeida, Alencar Luciana Magalhães Rebelo, Henriques Maria das Graças Muller de Oliveira, Barja-Fidalgo Thereza Christina, Follmer Cristian, Santos-Oliveira Ralph
Laboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Nuclear Engineering Institute, Brazilian Nuclear Energy Commission, Rio de Janeiro 21941906, RJ, Brazil.
Faculty of Pharmacy, Department of Radiopharmacy, Ege University, Bornova, Izmir 35040, Turkey.
Pharmaceutics. 2025 May 15;17(5):649. doi: 10.3390/pharmaceutics17050649.
: Lipoxins, particularly Lipoxin A4 (LXA4), are endogenous lipid mediators with potent anti-inflammatory and pro-resolving properties, making them promising candidates for the treatment of inflammatory and neurodegenerative disorders. However, their therapeutic application is limited by poor stability and bioavailability. This study aimed to develop and characterize nanomicelles encapsulating LXA4 (nano-lipoxin A4) to improve its pharmacological efficacy against Alzheimer's disease (AD), a neurodegenerative condition marked by chronic inflammation and beta-amyloid (Aβ) accumulation. : Nano-lipoxin A4 was synthesized using Pluronic F-127 as a carrier and characterized in terms of morphology, physicochemical stability, and in vitro activity against Aβ fibrils. Dissociation of Aβ fibrils was assessed via Thioflavin-T fluorescence assays and transmission electron microscopy. In vivo biodistribution and pharmacokinetic profiles were evaluated using technetium-99m-labeled nano-lipoxin A4 in rodent models. Hepatic biochemical parameters were also measured to assess potential systemic effects. : In vitro studies demonstrated that nano-lipoxin A4 effectively dissociated Aβ fibrils at concentrations of 50 nM and 112 nM. Electron microscopy confirmed the disruption of fibrillar structures. In vivo imaging revealed predominant accumulation in the liver and spleen, consistent with reticuloendothelial system uptake. Pharmacokinetic analysis showed a prolonged half-life (63.95 h) and low clearance rate (0.001509 L/h), indicating sustained systemic presence. Biochemical assays revealed elevated liver enzyme levels, suggestive of increased hepatic metabolism or potential hepatotoxicity. : Nano-lipoxin A4 exhibits significant therapeutic potential for Alzheimer's disease through effective modulation of Aβ pathology and favorable pharmacokinetic characteristics. However, the elevation in liver enzymes necessitates further investigation into systemic safety to support clinical translation.
脂氧素，尤其是脂氧素A4（LXA4），是具有强大抗炎和促消退特性的内源性脂质介质，使其成为治疗炎症性和神经退行性疾病的有前景的候选药物。然而，它们的治疗应用受到稳定性和生物利用度差的限制。本研究旨在开发并表征包裹LXA4的纳米胶束（纳米脂氧素A4），以提高其对阿尔茨海默病（AD）的药理疗效，AD是一种以慢性炎症和β-淀粉样蛋白（Aβ）积累为特征的神经退行性疾病。：使用普朗尼克F-127作为载体合成纳米脂氧素A4，并对其形态、物理化学稳定性以及对Aβ纤维的体外活性进行表征。通过硫黄素-T荧光测定法和透射电子显微镜评估Aβ纤维的解离情况。在啮齿动物模型中使用99m锝标记的纳米脂氧素A4评估体内生物分布和药代动力学概况。还测量了肝脏生化参数以评估潜在的全身影响。：体外研究表明，纳米脂氧素A4在50 nM和112 nM浓度下能有效解离Aβ纤维。电子显微镜证实了纤维状结构的破坏。体内成像显示主要在肝脏和脾脏中积累，与网状内皮系统摄取一致。药代动力学分析显示半衰期延长（63.95小时）和清除率低（0.001509 L/h），表明在体内持续存在。生化测定显示肝酶水平升高，提示肝脏代谢增加或潜在的肝毒性。：纳米脂氧素A4通过有效调节Aβ病理和良好的药代动力学特征，对阿尔茨海默病具有显著的治疗潜力。然而，肝酶升高需要进一步研究全身安全性以支持临床转化。
