Hybrid Lipid - Inorganic nanoparticles for drug delivery to the brain

混合脂质 - 用于向大脑输送药物的无机纳米颗粒

• 批准号: 2665477
• 金额: --
• 依托单位: University of Leeds
• 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-2665477
• 关键词: Hybrid; Lipid; Inorganic; nanoparticles; drug

Drug delivery to the brain is challenging and relies on crossing a semipermeable membrane known as the blood-brain barrier (BBB). The BBB is an endothelial cell monolayer that separates the blood from the cerebral central nervous system (CNS). This tight junction in the BBB presents a physical barrier to the permeability of the majority of drugs from the blood to the CNS when administered intravenously. Oxidative stress plays a significant role in the pathology of multiple neurodegenerative diseases such as Parkinson's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease and stroke. Certain inorganic nanoparticles (NPs) are powerful antioxidants with robust activity and it was recently shown that they are promising candidates for novel therapy of neurodegenerative diseases involving oxidative stress that can neutralize several important pathological reactive oxygen species that can lead to neurodegeneration. Whilst they show great therapeutic promise, their small size (3-4 nm) means they are rapidly cleared from the body, accumulate in the liver and spleen, are unable to reach the brain and show off-target toxicity. Lipid nanoparticles (LNPs) are a promising noninvasive strategy to protect drug payload and toxicity, and have been employed as delivery vehicles to treat many diseases such as cancer and recently in two COVID vaccine formulations. They can enhance penetration into the brain and although they show superior performance there are limited number of studies. LNPs offer advantages over current nanoformulations, including favourable drug payloads due to their high internal surface area, simple preparation protocols, superior ease of conjugation, biodegradability/ biocompatibility, and the ability to encapsulate hydrophobic and hydrophilic cargo. The aim of this project is to create colloidally stable soft matter formulations that encapsulate inorganic NPs into various novel LNPs (100-200 nm) developed in our labs. These hybrid lipidinorganic NPs will be characterized using Dynamic Light Scattering, Small Angle X-ray Scattering and cryo-TEM and long term stability studies. Encapsulation and release of the inorganic NPs will be assessed spectroscopically. The inherent heterogeneity within a nanomedicine formulation can lead to a range of behaviours and properties that influence the overall functionality of the product. We will investigate the heterogeneity of these soft matter formulations by asymmetric flow field flow fractionation (AF4) to separate LNPs into distinct subpopulations based on their size and shape, which are characterised by in-line multi-angle light scattering, UV-Vis spectroscopy and dynamic light scattering. The fractionated LNP subpopulations will also be characterized off-line to elucidate heterogeneities in drug-loading and release, which is crucial for performance.

药物递送到大脑是具有挑战性的，并且依赖于穿过被称为血脑屏障（BBB）的半透膜。BBB是将血液与大脑中枢神经系统（CNS）分离的内皮细胞单层。当静脉内给药时，BBB中的这种紧密连接对大多数药物从血液到CNS的渗透性提供了物理屏障。氧化应激在多种神经退行性疾病如帕金森病、肌萎缩侧索硬化症（ALS）、阿尔茨海默病和中风的病理学中起重要作用。某些无机纳米颗粒（NP）是具有强大活性的强大抗氧化剂，并且最近显示它们是用于涉及氧化应激的神经退行性疾病的新疗法的有希望的候选物，所述氧化应激可以中和可能导致神经退行性疾病的几种重要的病理活性氧。虽然它们显示出巨大的治疗前景，但它们的小尺寸（3-4 nm）意味着它们可以迅速从体内清除，在肝脏和脾脏中积累，无法到达大脑并显示出脱靶毒性。脂质纳米颗粒（LNP）是一种有前途的保护药物有效载荷和毒性的非侵入性策略，并且已被用作递送载体来治疗许多疾病，例如癌症，最近在两种COVID疫苗制剂中。它们可以增强对大脑的渗透，尽管它们显示出上级性能，但研究数量有限。LNP提供优于当前纳米制剂的优点，包括有利的药物有效载荷，这是由于它们的高内表面积、简单的制备方案、上级容易缀合、生物降解性/生物相容性以及包封疏水性和亲水性货物的能力。该项目的目的是创造胶体稳定的软物质配方，将无机纳米粒子封装到我们实验室开发的各种新型LNP（100-200 nm）中。将使用动态光散射、小角X射线散射和低温TEM以及长期稳定性研究来表征这些混合脂质无机NP。无机NP的包封和释放将通过光谱进行评估。纳米药物制剂中固有的异质性可能导致一系列影响产品整体功能的行为和特性。我们将通过非对称流场流分离（AF 4）研究这些软物质制剂的异质性，以根据其大小和形状将LNP分离成不同的亚群，其特征在于在线多角度光散射，紫外-可见光谱和动态光散射。分级分离的LNP亚群也将离线表征，以阐明载药和释放的异质性，这对性能至关重要。