Vargas-Barona Alondra, Bernáldez-Sarabia Johanna, Castro-Ceseña Ana B
Departamento de Innovación Biomédica, Centro de Investigación Científica y de Educación Superior de Ensenada, Baja California (CICESE), Carretera Ensenada- Tijuana No. 3918, Zona Playitas, C.P. 22860, Ensenada, Baja California, Mexico.
CONAHCYT-Departamento de Innovación Biomédica, Centro de Investigación Científica y de Educación Superior de Ensenada, Baja California (CICESE), Carretera Ensenada-Tijuana No. 3918, Zona Playitas, C.P. 22860, Ensenada, Baja California, Mexico.
J Mater Chem B. 2024 May 29;12(21):5085-5097. doi: 10.1039/d4tb00521j.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment associated with the accumulation of beta-amyloid protein (Aβ). Aβ activates glial cells in the brain, increasing the secretion of proinflammatory cytokines, which leads to neuroinflammation and neuronal death. Currently, there are no effective treatments that cure or stop its progression; therefore, AD is considered a global health priority. The main limitations are the low drug bioavailability and impermeability of the blood-brain barrier (BBB). Fortunately, nanomedicine has emerged as a promising field for the development of new nanosystems for the controlled and targeted delivery of drugs to the brain. Therefore, in this work, lipid-polymer hybrid nanoparticles (LPHNPs) conjugated with transferrin (Tf) to facilitate crossing the BBB and loaded with -acetylcysteine (NAC) for its anti-inflammatory effect were synthesized, and their physicochemical characterization was carried out. Subsequently, an model involving human astrocytes derived from induced pluripotent stem cells (iPSC) from an AD-diagnosed patient was developed, which was brought to a reactive state by stimulation with lipopolysaccharides (LPSs). The cell culture was treated with either Tf-conjugated LPHNPs loaded with NAC (NAC-Tf-LPHNPs) at 0.25 mg mL, or free NAC at 5 mM. The results showed that NAC-Tf-LPHNPs favorably modulated the expression of proinflammatory genes such as interleukin-1β (IL-1β), amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP). In addition, they reduced the secretion of the proinflammatory cytokines interleukin 6 (IL-6), IL-1β and interferon-gamma (INF-γ). Results for both cases were compared to the group of cells that did not receive any treatment. In contrast, free NAC only had this effect on the expression of IL-1β and the secretion of the cytokines IL-6 and INF-γ. These results indicate the potential of NAC-Tf-LPHNPs for AD treatment.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是与β-淀粉样蛋白（Aβ）积累相关的认知障碍。Aβ激活大脑中的神经胶质细胞，增加促炎细胞因子的分泌，进而导致神经炎症和神经元死亡。目前，尚无治愈或阻止其进展的有效治疗方法；因此，AD被视为全球卫生重点问题。主要限制在于药物生物利用度低以及血脑屏障（BBB）的不透性。幸运的是，纳米医学已成为一个有前景的领域，可用于开发新型纳米系统，以实现药物向大脑的可控靶向递送。因此，在本研究中，合成了与转铁蛋白（Tf）偶联以促进血脑屏障穿越并负载有具有抗炎作用的N-乙酰半胱氨酸（NAC）的脂质-聚合物杂化纳米颗粒（LPHNPs），并对其进行了理化表征。随后，建立了一个模型，该模型涉及源自一名AD诊断患者的诱导多能干细胞（iPSC）的人星形胶质细胞，通过用脂多糖（LPS）刺激使其进入反应状态。细胞培养物分别用浓度为0.25 mg/mL的负载NAC的Tf偶联LPHNPs（NAC-Tf-LPHNPs）或5 mM的游离NAC进行处理。结果表明，NAC-Tf-LPHNPs有利地调节了促炎基因如白细胞介素-1β（IL-1β）、淀粉样前体蛋白（APP）和胶质纤维酸性蛋白（GFAP）的表达。此外，它们减少了促炎细胞因子白细胞介素6（IL-6）、IL-1β和干扰素-γ（INF-γ）的分泌。将这两种情况的结果与未接受任何处理的细胞组进行了比较。相比之下，游离NAC仅对IL-1β的表达以及细胞因子IL-6和INF-γ的分泌有这种作用。这些结果表明NAC-Tf-LPHNPs在AD治疗方面具有潜力。
