Zheng Xiaoyao, Zhang Chi, Guo Qian, Wan Xu, Shao Xiayan, Liu Qingfeng, Zhang Qizhi
Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, 201203, People's Republic of China.
Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, 201203, People's Republic of China; Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, People's Republic of China.
Int J Pharm. 2017 Jun 15;525(1):237-248. doi: 10.1016/j.ijpharm.2017.04.033. Epub 2017 Apr 18.
Alzheimer's disease (AD) is the most common form of dementia and is characterized by the cerebral accumulation of extracellular amyloid plaques. In a previous study, this histopathological hallmark was used as a target on a dual-functional nanoparticle (TQNP) to deliver biotechnological drugs, such as the H102 peptide, a β-sheet breaker, to AD lesions precisely. This delivery system could reduce the amyloid-β (Aβ) burden in the brains of AD model mice, as well as ameliorated the memory impairment of the mice. Regretfully, the mechanism how nanoparticles penetrated the BBB and subsequently targeted to the plaques is still unclear. In this study, the internalization, subcellular fate and transportation of the nanoparticles on bEnd.3 cells and an in vitro BBB model, demonstrated that TQNP could be taken up through various routes, including caveolae-mediated endocytosis, suggesting that some of TQNP were able to cross the BBB intact. Then, the TQNP were visualized to specifically bind to the Aβ plaques. TQNP targeting to amyloid plaques might lead to enhanced therapeutic efficacy, which was further evaluated in APP/PS1 transgenic mice. The TQNP/H102 obtained better ability in decreasing amyloid plaques, increasing Aβ-degrading enzymes, reducing tau protein phosphorylation, protecting synapses and improving the spatial learning and memory of transgenic mice than nanoparticles modified with a single ligand. And good biocompatibility of TQNP was indicated with subacute toxicity assays. In conclusion, TQNP was a valuable nanodevice for the precise delivery for biotechnological drugs to treat AD.
阿尔茨海默病（AD）是最常见的痴呆形式，其特征是细胞外淀粉样斑块在大脑中积累。在先前的一项研究中，这种组织病理学特征被用作双功能纳米颗粒（TQNP）的靶点，以将生物技术药物，如β-折叠破坏剂H102肽，精确递送至AD病变部位。这种递送系统可以减轻AD模型小鼠大脑中的淀粉样β蛋白（Aβ）负担，并改善小鼠的记忆障碍。遗憾的是，纳米颗粒如何穿透血脑屏障（BBB）并随后靶向斑块的机制仍不清楚。在本研究中，纳米颗粒在bEnd.3细胞和体外血脑屏障模型上的内化、亚细胞命运和运输表明，TQNP可以通过多种途径被摄取，包括小窝介导的内吞作用，这表明一些TQNP能够完整地穿过血脑屏障。然后，观察到TQNP特异性结合Aβ斑块。靶向淀粉样斑块的TQNP可能会提高治疗效果，这在APP/PS1转基因小鼠中得到了进一步评估。与单配体修饰的纳米颗粒相比，TQNP/H102在减少淀粉样斑块、增加Aβ降解酶、减少tau蛋白磷酸化、保护突触以及改善转基因小鼠的空间学习和记忆方面具有更好的能力。亚急性毒性试验表明TQNP具有良好的生物相容性。总之，TQNP是一种有价值的纳米装置，可用于将生物技术药物精确递送至治疗AD的部位。
