Technologies for the Treatment of Brain Diseases

脑部疾病治疗技术

• 批准号: EP/G061483/1
• 负责人: Ijeoma Uchegbu
• 金额: $ 94.74万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FG061483%2F1
• 关键词: Technologies; Treatment; Brain; Diseases

The Grand Challenge is the treatment of brain diseases. Brain diseases span pain, sleep disorders, schizophrenia, mood disorders and neurodegenerative conditions. At any time 450 million persons worldwide are living with mental, neurological or behavioural illnesses and 24 million people worldwide suffer from dementias. The treatment of brain diseases is hampered by the blood brain barrier (BBB), a barrier between the blood and the brain which does not permit the passage of most drug molecules, due to the tightness of the intercellular capillary junctions, low uptake activity of capillary cells and the activity of efflux transporters. Previous attempts to target drugs to the brain and cross the BBB have involved the use of targeting ligands, e.g. mouse monoclonal antibodies for carrier mediated uptake or the inhibition of the above mentioned efflux transporters. However all of the particulate-based strategies (including the use of mouse monoclonal antibodies) that have been investigated over the last two decades have yet to yield any clinical products and the inhibition of the high capacity efflux transporters, which incidentally are not merely confined to the BBB, is not a viable clinical option. Our multidisciplinary consortium drawn from academia and industry (GSK) propose a new nanoscience based strategy founded on two recent significant findings: a) chitosan amphiphile based nanoparticles significantly increase the central activity of hydrophobic and peptides drugs via the intravenous and crucially oral routes, b) apolipoprotein E targeted nanoparticles bypass the brain capillary efflux transporters and cross the BBB, increasing drug delivery to the brain. The project aims to use these data to create an optimised nanotechnology brain delivery platform for peptides and low molecular weight drugs with low brain permeability. These drug classes represent the bulk of the compounds which are trapped in the drug development bottleneck due to: a) their poor brain exposure and b) the absence of suitable brain targeting strategies. Candidate drugs to be used are potential treatments for schizophrenia, pain and sleep disorders. These compounds and their potential indications are particularly relevant to the call (targeting psychiatric diseases) and a specific output of the project is a candidate medicine for the treatment of psychiatric or neurological disorders. The project will involve a significant level of particle engineering, where particle matrix chemistry, surface chemistry (including the discovery and evaluation of other BBB targeting peptides) and particle size will be systematically varied and the impact of these variations tested using in vitro and animal models. The resulting pharmacokinetic, pharmacodynamic and mechanistic data will inform the optimisation of the platform which is the ultimate goal of the project. Fundamentally the mechanism of brain permeation of the drug cargoes will be studied and elucidated en route to the optimised nanosystem and this will also fulfil a requirement of regulators and health providers, who desire an underlying mechanistic basis for new health technologies. Stage 2 of the project (GSK fully supported) will focus on the development of a clinical medicine based on the nanotechnology platform.Public engagement activities will occur via our nanomedicines.org website and also via public communication of science events. The key beneficiaries of the project will be patients, carers and the pharmaceutical industry as the platform will pave the way for novel therapeutic targets to be exploited. The engagement of scientists, with a past history of collaboration and a strong track record in nanoscience innovation, therapeutic target discovery, lead identification, drug targeting, translating scientific concepts to clinical products and basic brain physiology makes the consortium ideally suited to deliver the nanoscience based drug targeting goals of the Grand Challenge.

大挑战是治疗脑部疾病。脑部疾病包括疼痛、睡眠障碍、精神分裂症、情绪障碍和神经退行性疾病。全世界任何时候都有4.5亿人患有精神、神经或行为疾病，全世界有2 400万人患有痴呆症。脑疾病的治疗受到血脑屏障（BBB）的阻碍，血脑屏障是血液和脑之间的屏障，由于细胞间毛细血管连接的紧密性、毛细血管细胞的低摄取活性和外排转运蛋白的活性，血脑屏障不允许大多数药物分子通过。先前将药物靶向脑并穿过BBB的尝试涉及使用靶向配体，例如用于载体介导的摄取或抑制上述外排转运蛋白的小鼠单克隆抗体。然而，在过去二十年中已经研究的所有基于颗粒的策略（包括使用小鼠单克隆抗体）尚未产生任何临床产品，并且抑制高容量外排转运蛋白（顺便说一下，其不仅限于BBB）不是可行的临床选择。我们来自学术界和工业界的多学科联盟（GSK）提出了一项新的基于纳米科学的战略，该战略基于最近的两项重大发现：a）基于壳聚糖两亲物的纳米颗粒通过静脉内和关键的口服途径显著增加疏水性和肽类药物的中枢活性，B）载脂蛋白E靶向纳米颗粒绕过脑毛细血管流出转运蛋白并穿过BB B，增加药物向脑的递送。该项目旨在利用这些数据为具有低脑渗透性的肽和低分子量药物创建优化的纳米技术脑递送平台。这些药物类别代表了由于以下原因而陷入药物开发瓶颈的大部分化合物：a）其不良的脑暴露和B）缺乏合适的脑靶向策略。待用的候选药物是治疗精神分裂症、疼痛和睡眠障碍的潜在药物。这些化合物及其潜在适应症与这一呼吁（针对精神疾病）特别相关，该项目的一项具体产出是治疗精神或神经疾病的候选药物。该项目将涉及颗粒工程的重要水平，其中颗粒基质化学，表面化学（包括其他BBB靶向肽的发现和评估）和粒度将系统地变化，并使用体外和动物模型测试这些变化的影响。由此产生的药代动力学、药效学和机制数据将为平台的优化提供信息，这是该项目的最终目标。从根本上讲，药物货物的脑渗透机制将在优化纳米系统的过程中进行研究和阐明，这也将满足监管机构和医疗服务提供者的要求，他们希望为新的医疗技术提供潜在的机制基础。该项目的第二阶段（GSK全力支持）将专注于开发基于纳米技术平台的临床医学。公众参与活动将通过我们的网站nanomedicines.org以及科学活动的公众交流进行。该项目的主要受益者将是患者、护理人员和制药行业，因为该平台将为开发新的治疗靶点铺平道路。科学家的参与，与过去的合作历史和在纳米科学创新，治疗靶点发现，铅识别，药物靶向，将科学概念转化为临床产品和基本脑生理学的良好记录，使该联盟非常适合提供基于纳米科学的药物靶向目标的大挑战。

项目成果

Label-free imaging of polymeric nanomedicines using coherent anti-stokes Raman scattering microscopy

• DOI: 10.1002/jrs.3170
• 发表时间: 2012-05-01
• 期刊: JOURNAL OF RAMAN SPECTROSCOPY
• 影响因子: 2.5
• 作者: Garrett, N. L.;Lalatsa, A.;Moger, J.
• 通讯作者: Moger, J.

Abstract 4519: Lomustine nanoparticles are effective brain cancer treatments.

摘要 4519：洛莫司汀纳米颗粒是有效的脑癌治疗方法。

• DOI: 10.1158/1538-7445.am2013-4519
• 发表时间: 2013
• 期刊: Cancer Research
• 影响因子: 11.2
• 作者: Fisusi F

Abstract 5530: Chitosan amphiphile nanoparticles reduced the myelosuppressive effects of lomustine

摘要 5530：壳聚糖两亲纳米粒子降低洛莫司汀的骨髓抑制作用

• DOI: 10.1158/1538-7445.am2015-5530
• 发表时间: 2015
• 期刊: Cancer Research
• 影响因子: 11.2
• 作者: Fisusi F

Nanoparticulate Mycophenolic Acid Eye Drops - Analytical Validation of a High Performance Liquid Chromatography Assay and Stability Studies.

纳米颗粒霉酚酸滴眼液 - 高效液相色谱测定和稳定性研究的分析验证。

• DOI: 10.2174/2211738509666210111161110
• 发表时间: 2021
• 期刊: Pharmaceutical nanotechnology
• 作者: Al-Kulabi A