Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Nanomedicine. 2010 Jun;6(3):427-41. doi: 10.1016/j.nano.2009.11.007. Epub 2010 Jan 4.
Identification of pharmacological and toxicological profiles is of critical importance for the use of nanoparticles as drug carriers in nanomedicine and for the biosafety evaluation of environmental nanoparticles in nanotoxicology. Here we show that lysosomes are the pharmacological target organelles for single-walled carbon nanotubes (SWCNTs) and that mitochondria are the target organelles for their cytotoxicity. The gastrointestinally absorbed SWCNTs were lysosomotropic but also entered mitochondria at large doses. Genes encoding phosphoinositide-3-kinase and lysosomal-associated membrane protein 2 were involved in such an organelle preference. SWCNT administration resulted in collapse of mitochondrial membrane potentials, giving rise to overproduction of reactive oxygen species, leading to damage of mitochondria, which was followed by lysosomal and cellular injury. Based on the dosage differences in target organelles, SWCNTs were successfully used to deliver acetylcholine into brain for treatment of experimentally induced Alzheimer disease with a moderate safety range by precisely controlling the doses, ensuring that SWCNTs preferentially enter lysosomes, the target organelles, and not mitochondria, the target organelles for SWCNT cytotoxicity.
Single wall carbon nanotubes (SWCNT) could make excellent targeted delivery systems for pharmaceuticals. Inside the cells, lysosomes are the pharmacological target organelles of SWCNT, but in large doses mitochondria also take up SWCNT and mitochondrial toxicity becomes the reason for overall toxicity of this approach. In this paper, SWCNT were successfully used to deliver acetylcholine in Alzheimer's disease brains with high safety range by controlling the doses to ensure lysosomal but not mitochondrial targeting.
鉴定药物学和毒理学特性对于将纳米粒子作为药物载体应用于纳米医学以及对于纳米毒理学中环境纳米粒子的生物安全性评估是至关重要的。在此，我们发现溶酶体是单壁碳纳米管（SWCNTs）的药物作用靶细胞器，而线粒体是其细胞毒性的靶细胞器。胃肠道吸收的 SWCNTs 具有溶酶体趋向性，但在大剂量时也进入线粒体。参与这种细胞器选择性的基因有编码磷酯酰肌醇-3-激酶和溶酶体相关膜蛋白 2 的基因。SWCNT 给药导致线粒体膜电位崩溃，引起活性氧的过度产生，导致线粒体损伤，随后发生溶酶体和细胞损伤。基于靶细胞器的剂量差异，SWCNTs 被成功地用于将乙酰胆碱递送至大脑，用于治疗实验性诱导的阿尔茨海默病，通过精确控制剂量，确保 SWCNTs 优先进入溶酶体（靶细胞器），而不是线粒体（SWCNT 细胞毒性的靶细胞器），从而实现了适度的安全范围。
单壁碳纳米管（SWCNT）可以成为药物的理想靶向递药系统。在细胞内，溶酶体是 SWCNT 的药物作用靶细胞器，但在大剂量时，线粒体也摄取 SWCNT，线粒体毒性成为这种方法整体毒性的原因。在本文中，通过控制剂量，SWCNT 成功地用于将乙酰胆碱递送至阿尔茨海默病大脑，具有很高的安全性，以确保溶酶体而非线粒体靶向。
