Nanoparticles for the Targeted Delivery of Therapeutic Agents to the Brain for the Treatment of Dementias.

该项目的重点是开发纳米技术，有针对性地提供阿尔茨海默病的新疗法，阿尔茨海默病是老年人痴呆的主要原因。痴呆症最常见的症状是逐渐丧失记忆力、神志不清，以及个性、情绪和行为的改变。目前，英国约有70万名痴呆症患者，其中约45万人患有阿尔茨海默病。痴呆症没有治愈的方法，只有治疗症状并暂时稳定疾病进展的药物，因此患者变得更加依赖护理。2002年，痴呆症患者的正规医疗服务(例如，住宿护理、NHS支持服务)的成本为40亿美元，这是令人敬畏的，预计到2031年将增长到130亿美元。然而，当考虑到专利家属的非正式护理费用时，估计成本将升至约170亿英镑。病人护理对照顾者职业生涯的影响还带来了进一步的经济和社会损失。因此，痴呆症对英国和其他国家来说是一个日益严重的医疗、社会和经济问题。目前对痴呆症的理解和治疗的研究活动水平并没有反映出日益严峻的挑战的巨大程度。痴呆症是导致晚年残疾的主要原因之一，在所有60岁以上的残疾人士中，痴呆症占11.2%，相比之下，癌症占2.4%。然而，自2002年以来，发表的关于残疾的研究论文中，只有1.4%涉及痴呆症，而癌症的这一比例为23.5%。因此，增加痴呆症研究经费和活动是当务之急。在这个项目中，我们的目标是利用纳米技术来设计和提供治疗阿尔茨海默病的新疗法。纳米颗粒是人工合成的化学成分的配方，混合成小于100纳米的颗粒后自组装。它们可以用来包装各种药物，包括基因、蛋白质和RNA分子。将被设计和合成的纳米颗粒组件将包括具有智能特性的新型多肽和脂类，例如受体靶向、隐形涂层、用于拆卸的生物响应连接物和生物兼容性。血脑屏障阻碍了纳米颗粒从血液循环进入大脑的过程，因此我们将优化一种名为对流增强输送(CED)的方法。在CED中，通过恒定压力下的细针将试剂直接注射到大脑中，物理上绕过了血脑屏障。CED已经被用于治疗，实现了在大脑中的广泛扩散，但还没有优化为纳米颗粒的输送。该项目结合了与CED相关的纳米颗粒材料和脑生物学的基础研究，以及利用磁共振对纳米颗粒配方和CED介导的弥散研究的更多应用研究。这项研究的成果将是一种纳米颗粒平台技术和输送方法，与阿尔茨海默病和其他形式的痴呆症的一系列治疗选择兼容。研究团队由化学、药物和纳米颗粒配方方面的科学专家以及脑病理学、外科手术和实验性临床试验方面的临床专业知识组成，有能力在这一项目和未来对阿尔茨海默病的第二阶段治疗研究中取得成功。这一新能力可能会改变痴呆症患者的管理，给英国社会和经济带来巨大的潜在好处。

This project focuses on the development of nanotechnologies for the targeted delivery of novel therapies for Alzheimer's disease, the major cause of dementia in the elderly. The most common symptoms of dementias are gradual memory loss, confusion, and changes in personality, mood and behaviour. There are currently about 700,000 dementia patients in the UK and approximately 450,000 of those have Alzheimer's disease. There are no cures for dementias, only drugs that treat the symptoms and temporarily stabilize the disease progression so patients become more dependent on care. The cost of formal healthcare services (e.g., residential care, NHS support services) for dementia patients at 4Bn in 2002 are formidable, and expected to grow to 13Bn by 2031. However, when informal care contributions from families of patents are considered, estimated costs escalate to about 17Bn. There is a further economic and social toll from the impact of patient care on the careers of carers. Dementia is therefore a growing medical, social and economic problem for the UK and beyond. The current level of research activity into the understanding and treatment of dementias does not reflect the enormity of the growing challenge. Dementia is one of the major causes of disability in later life, contributing 11.2% of all years lived with disability over the age of 60, compared to 2.4% for cancer. Since 2002, however, only 1.4% of published research papers on disabilities concerned dementias, compared to 23.5% for cancers. Increased research funding and activity in dementias is therefore an urgent priority. We aim in this project to harness nanotechnologies for the design and delivery of new therapeutics for the treatment of Alzheimer's disease. Nanoparticles are formulations of synthetic, chemical components that self-assemble on mixing into particles of less than 100 nm. They can be used to package a variety of drugs, including genes, proteins and RNA molecules. The nanoparticle components that will be designed and synthesised will comprise novel peptides and lipids with smart properties, such as receptor targeting, stealth coatings, bioresponsive linkers for disassembly, and biocompatibility. The uptake of nanoparticles into the brain from the circulation is impeded by the blood brain barrier so we will optimise a method called convection enhanced delivery (CED). In CED the blood-brain barrier is physically bypassed by injecting reagents directly into the brain through a fine needle under constant pressure. CED has already been used to administer therapeutics, achieving widespread dispersal through the brain, but has not been optimised for nanoparticle delivery. The project combines basic studies into nanoparticle materials and biology of the brain in relation to CED, and more applied studies into nanoparticle formulation and CED-mediated dispersal studies using MRI. The output of this study will be a nanoparticle platform technology and delivery method compatible with a range of therapeutic options for Alzheimer's disease and other forms of dementia. The research team comprises scientific experts in chemistry, drug and nanoparticle formulations as well as clinical expertise in brain pathology, surgery and experimental clinical trials, and has the capabilities to succeed both in this project and a future Stage 2 therapeutic study into Alzheimer's disease. This new capability could transform the management of patients with dementias with enormous potential benefits to UK society and the economy.