Nanoparticle iron chelators: A new therapeutic approach in Alzheimer disease and other neurologic disorders associated with trace metal imbalance

Accumulating evidence suggests that oxidative stress may be a major etiologic factor in initiating and promoting neurodegeneration in Alzheimer disease. Contributing to this, there is a dyshomeostasis of metal ions in Alzheimer disease with abnormally high levels of redox-active metals, particularly iron, in affected areas of the brain. Although it is unclear whether metal excesses are the sole cause of oxidative stress and neurodegeneration or a by-product of neuronal loss, the finding that metal chelators can partially solubilize amyloid-β deposits in Alzheimer disease suggests a promising therapeutic role for chelating agents. However, the blood–brain barrier and toxicity of known chelators limit their utility. In this study, we suggest that covalent conjugation of iron chelators with nanoparticles may help overcome the limitations in blood–brain barrier permeability of existing chelation therapy. Using in vitro studies, we have shown that a chelator–nanoparticle system and the chelator–nanoparticle system complexed with iron, when incubated with human plasma, preferentially adsorb apolipoprotein E and apolipoprotein A-I, that would facilitate transport into and out of the brain via mechanisms used for transporting low-density lipoprotein. Our studies suggest a unique approach, utilizing nanoparticles, to transport chelators and chelator–metal complexes in both directions across the blood–brain barrier, thus providing safer and more effective chelation treatment in Alzheimer disease and other neurodegenerative diseases.