Pharmacological and toxicological target organelles and safe use of single-walled carbon nanotubes as drug carriers in treating Alzheimer disease.
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.


BACKGROUND
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.
Yang
Zhong
Z
Key Laboratory of Nanopharmacology and Nanotoxicology, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Zhang
Yingge
Y
Yang
Yanlian
Y
Sun
Lan
L
Han
Dong
D
Li
Hong
H
Wang
Chen
C
D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000633:toxicity*; D006304:Health Status; D007408:Intestinal Absorption / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008568:Memory / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D050997:Nanomedicine / Q000379:methods*; D037742:Nanotubes, Carbon / Q000009:adverse effects* / Q000633:toxicity* / Q000648:ultrastructure; D009928:Organ Specificity / Q000187:drug effects; D015203:Reproducibility of Results; D013059:Spectrum Analysis, Raman; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
D004337:Drug Carriers; D037742:Nanotubes, Carbon; D000109:Acetylcholine