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因子，并且在许多神经退行性疾病中起关键作用，例如，阿尔茨海默病和威尔逊病。特别是在阿尔茨海默病的情况下，向大脑外源性供应Cu是解决这种缺乏症状的治疗方法之一。然而，铜需要转运到中枢神经系统（CNS）和绕过血脑屏障（BBB），这仍然是一个未解决的问题。用于此目的的有前途的系统是纳米载体，其可以选择性地结合Cu离子并响应于生化触发器（例如病理组织中存在的改变的pH或离子强度）将它们特异性地释放到细胞环境中。在这个合作项目中，核-单壳（CS）或核-多壳（CMS）纳米载体将被设计为具有超支化聚甘油（hPG）核。为了选择性地结合Cu（II），不同的铜结合氨基配体将作为壳连接。聚（乙二醇）链将连接到核或壳系统，以分别产生CS和CMS架构。然后将研究这些新的纳米转运蛋白的结构组织、自组装行为和金属结合能力。将进行大量的物理化学研究，以探讨铜的捕获和释放的机制。最后，将进行生化试验，以阐明细胞毒性、摄取和区室化。

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.