Development and neuroprotective testing of nanocarrier formulations for intranasal administration of curcumin derivatives CNB-001, J-147 and T-006

用于姜黄素衍生物 CNB-001、J-147 和 T-006 鼻内给药的纳米载体制剂的开发和神经保护测试

• 批准号: 2546737
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2546737
• 关键词: Development; neuroprotective; testing; nanocarrier; formulations

Curcumin is a natural compound with anti-inflammatory, anti-oxidant and neuroprotectivecharacteristics. It attenuates mitochondrial dysfunction and reduces damage in adult andneonatal ischemia/reperfusion and inflammation models. The major limitation to clinicalimplementation of curcumin is its extremely low water-solubility (0.0004mg/ml) andbioavailability, the lack of identified molecular target and its pan essay interferencecharacteristics. CNB-001, J-147 and T-006 are synthetic curcumin analogs, thus allowingconsistency in production and purity. Although all three derivatives have better characterizedmolecular targets and are already trialed in neurodegeneration and stroke, they possess lowwater solubility and dissolve in DMSO, which is toxic for humans. Additionally, they have beenapplied orally or intravenously, which limits delivery to the brain through systemicelimination, and intranasal route of administration has not been implemented. Intranasalapplication is non-invasive, allows penetration through the blood brain barrier, it is quicker forbrain delivery through the trigeminal and olfactory routes, and by-passes peripheralelimination. Moreover, intranasal delivery is 10-fold more effective than systemicadministration and is thus more clinically relevant. This project aims to repurpose drugs thatare already in clinical testing and to develop novel nanoparticle formulations of CNB-001,J-147 and T-006 for minimally invasive intranasal application.The project will assess in vivo the pharmacokinetics of the most successful formulationsgenerated and tested in vitro for toxicity in the rotation project. Serum and brainconcentration of CNB-001, J-147 and T-006 post-intranasal administration of the nanoparticleformulations applied in naïve neonatal and adult mice will be assessed through HPLC.The formulations with best pharmacokinetics for each derivative will be histologically andbehaviourally assessed for short- and long-term in vivo neuroprotection when appliedintranasally in mouse models of neonatal hypoxia-ischaemia (Rocha-Ferreira et al., 2019) andadult facial nerve axotomy, where previously the Hristova lab has observed neuroprotectionwith systemic curcumin administration.

姜黄素是一种具有抗炎、抗氧化和神经保护特性的天然化合物。它可以减轻线粒体功能障碍并减少成人和新生儿缺血/再灌注和炎症模型的损伤。姜黄素临床应用的主要限制是其极低的水溶性（0.0004mg/ml）和生物利用度、缺乏确定的分子靶点及其泛文章干扰特性。 CNB-001、J-147 和 T-006 是合成姜黄素类似物，因此可以实现生产和纯度的一致性。尽管这三种衍生物都具有更好的分子靶标特征，并且已经在神经退行性疾病和中风中进行了试验，但它们的水溶性较低，并且溶解在对人类有毒的 DMSO 中。此外，它们已被口服或静脉注射，这限制了通过全身消除向大脑的递送，并且尚未实施鼻内给药途径。鼻内应用是非侵入性的，可以穿透血脑屏障，通过三叉神经和嗅觉途径更快地进行脑输送，并绕过外周消除。此外，鼻内给药的效率是全身给药的10倍，因此更具临床意义。该项目旨在重新利用已经在临床测试中的药物，并开发 CNB-001、J-147 和 T-006 的新型纳米颗粒制剂，用于微创鼻内应用。该项目将评估轮换项目中生成和体外毒性测试的最成功制剂的体内药代动力学。将通过 HPLC 评估鼻内施用纳米颗粒制剂后 CNB-001、J-147 和 T-006 的血清和脑浓度应用于幼年和成年小鼠。每种衍生物具有最佳药代动力学的制剂将进行组织学和行为评估，以评估鼻内应用时的短期和长期体内神经保护作用。 新生儿缺氧缺血小鼠模型（Rocha-Ferreira 等人，2019）和成人面神经轴突切除术，Hristova 实验室此前曾观察到全身性姜黄素给药的神经保护作用。