Chemo-enzymatic synthesis of multivalent dendritic architectures for the control of neurodegenerative disorders

用于控制神经退行性疾病的多价树突结构的化学酶合成

• 批准号: 323365372
• 负责人: Professor Dr. Rainer Haag
• 金额: --
• 依托单位: Department of Chemistry
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/323365372?language=en
• 关键词: Chemo; enzymatic; synthesis; multivalent; dendritic

Alzheimers disease (AD) is a progressive neurodegenerative disease that affects more than 30 million people worldwide. Neuro inflammation, characterized by excessive glial activation and overproduction of proinflammatory cytokine and chemokines, plays a critical role in the pathogenesis of neurodegeneration in AD and related neurodegenerative disorders. One of the hallmarks of AD is the aggregation of the amyloid beta peptide, which forms amyloid plaques in the brain. Metal ions such as Cu(II) have been proposed to play a role in amyloid formation and the onset of this progressive neurodegenerative disorder. Regulation of copper homeostasis is one of the potential strategies for the design of drug candidates for the treatment of AD. Earlier studies in animals have reported that normalized or elevated Cu(II) levels can inhibit or even remove AD related pathological plaques. Another possibility to validate the regulation of copper homeostasis in an AD brain is to use appropriate chelators capable of copper ion transfer from amyloid-beta peptide to regular proteins via competitive binding and release. The ability of such ligands to behave as vehicle ligands for a monovalent binding strategy has been attempted in vitro in the literature. However, the blood brain barrier (BBB) and neurotoxicity of many traditional metal chelators has limited their utility in AD or other neurodegenerative disorders. Only 5% of the drugs listed in the Comprehensive Medicinal Chemistry database target the CNS. Therefore, the transport of Cu ions / chelators over the BBB is a critical issue for our therapeutic approach. Nanoparticle delivery systems are known to cross the blood brain barrier and this has led us to investigate whether chelators delivered conjugated to nanoparticles could act to reverse metal ion induced protein precipitation. Dendritic nanoparticles (NP) have recently been reported for the transport of Cu(II) ions across the blood brain barrier (BBB) in the laboratory of one of the collaborators (Haag, FUB). Although the copper transport was dramatically increased in an in vitro BBB model, yet the dendritic copper complex was too instable in vivo. Herein it is proposed to extend the study in multiple dimensions. We propose the design of more stable but cleavable copper complexes within nanometer sized transporters that may be beneficial because they can be tailored to optimize their properties, such as hydrodynamic size, surface charges, and conductive transport, to the area of the intended application.

阿尔茨海默病（AD）是一种进行性神经退行性疾病，影响全球3000多万人。神经炎症以胶质细胞过度激活和促炎细胞因子和趋化因子过度产生为特征，在AD和相关神经退行性疾病的神经退行性疾病发病机制中发挥着关键作用。AD的特征之一是淀粉样β肽的聚集，其在脑中形成淀粉样斑块。金属离子如Cu（II）已被提出在淀粉样蛋白形成和这种进行性神经退行性疾病的发作中发挥作用。铜稳态的调节是设计用于治疗AD的候选药物的潜在策略之一。早期的动物研究已经报道，正常或升高的Cu（II）水平可以抑制甚至消除AD相关的病理性斑块。验证AD脑中铜稳态调节的另一种可能性是使用能够通过竞争性结合和释放将铜离子从淀粉样蛋白-β肽转移到常规蛋白质的适当螯合剂。在文献中，已经尝试了这种配体作为单价结合策略的载体配体的能力。然而，许多传统金属螯合剂的血脑屏障（BBB）和神经毒性限制了它们在AD或其他神经退行性疾病中的应用。综合药物化学数据库中列出的药物中只有5%靶向CNS。因此，Cu离子/螯合剂在BBB上的转运是我们治疗方法的关键问题。已知纳米颗粒递送系统可以穿过血脑屏障，这使得我们研究与纳米颗粒缀合的螯合剂是否可以逆转金属离子诱导的蛋白质沉淀。树突状纳米颗粒（NP）最近在合作者之一（Haag，FUB）的实验室中被报道用于运输Cu（II）离子穿过血脑屏障（BBB）。虽然在体外血脑屏障模型中铜转运显著增加，但树突状铜复合物在体内太不稳定。因此，建议在多个维度上扩展研究。我们提出了更稳定的，但可裂解的铜络合物的纳米尺寸的运输，这可能是有益的，因为它们可以被定制，以优化其性能，如流体动力学大小，表面电荷，和导电运输，预期的应用领域的设计。

项目成果

Synthesis of non-ionic and enzyme-responsive bolaamphiphiles for drug delivery applications

• DOI: 10.1016/j.eurpolymj.2018.10.007
• 发表时间: 2018-12-01
• 期刊: EUROPEAN POLYMER JOURNAL
• 影响因子: 6
• 作者: Prasad, Suchita;Achazi, Katharina;Sharma, Sunil K.
• 通讯作者: Sharma, Sunil K.

Non-ionic PEG-Oligoglycerol Dendron Conjugated Nano-carriers for Transdermal Delivery.

• DOI: 10.1016/j.ijpharm.2020.119212
• 发表时间: 2020-03
• 期刊: International journal of pharmaceutics
• 影响因子: 5.8
• 作者: Rashmi;F. Zabihi;A. Singh;K. Achazi;B. Schade;S. Hedtrich;R. Haag;Sunil K. Sharma

Dendrimer-based micelles as cyto-compatible nanocarriers

• DOI: 10.1039/c9nj02612f
• 发表时间: 2019-08-14
• 期刊: NEW JOURNAL OF CHEMISTRY
• 影响因子: 3.3
• 作者: Parshad, Badri;Yadav, Preeti;Sharma, Sunil K.
• 通讯作者: Sharma, Sunil K.