Dendritic Nanocarriers for the Selective and Targeted Metal Ion Transport over Biological Barriers

铜（Cu）是许多金属酶的重要生物辅助因子，在许多神经退行性疾病，如阿尔茨海默病和威尔逊病中起着关键作用。特别是在阿尔茨海默病的情况下，外源性向脑供应铜是解决这类缺乏症状的治疗方法之一。然而，铜需要被转运到中枢神经系统（CNS）并绕过血脑屏障（BBB），这是一个尚未解决的问题。有希望实现这一目的的系统是纳米载体，它可以选择性地结合cu离子，并根据生化触发因素（如病理组织中存在的pH值或离子强度的改变）特异性地将它们释放到细胞环境中。在这个合作项目中，核心-单壳（CS）或核心-多壳（CMS）纳米载体将被设计成超支化聚甘油（hPG）核心。为了选择性地结合Cu(II)，不同的铜结合氨基配体将作为一个壳体附着在一起。聚乙二醇链将连接到核心系统或壳系统，分别生成CS和CMS结构。这些新的纳米转运体将被研究其结构组织、自组装行为和金属结合能力。将开展大量的物理化学研究来探索铜的捕获和释放机制。最后，将进行生化试验来阐明细胞毒性、摄取和区隔化。

Copper (Cu) is an important biological cofactor for a number of metalloenzymes and plays a key role in many neurodegenerative diseases, e.g., Alzheimer’s disease and Wilson’s disease. Particularly in case of Alzheimer’s diseases, exogenous supply of Cu to brain is one of the therapeutic approaches for addressing such deficiency symptoms. However, Cu needs to be transported into the central nervous system (CNS) and bypass the blood-brain-barrier (BBB), which remains an unsolved problem. Promising systems for this purpose are nanocarriers, which can bind Cu-ions selectively and release them specifically into the cellular environment in response to biochemical triggers, such as altered pH or ionic strength that is existing in the pathological tissues. In this collaborative project, core-single shell (CS) or core-multishell (CMS) nanocarriers will be designed with a hyperbranched polyglycerol (hPG) core. In order to bind Cu(II) selectively, different copper binding amino ligands will be attached as a shell. Poly(ethylene glycol)-chains will be linked either to the core or to the shell system to generate CS and CMS architectures respectively. These new nanotransporters will then be investigated for their structural organization, self-assembling behavior and metal binding capacity. Substantial physico-chemical investigation will be carried out to explore the mechanism of Cu-entrapment and release. Finally, biochemical tests will be performed to elucidate cellular toxicity, uptake and compartmentalization.