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-beta 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.
Liu
Gang
G
Department of Radiology, University of Utah, Salt Lake City, UT 84102, USA. gang.liu@m.cc.utah.edu
Men
Ping
P
Harris
Peggy L R
PL
Rolston
Raj K
RK
Perry
George
G
Smith
Mark A
MA
D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D016632:Apolipoprotein A-I / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D001921:Brain / Q000187:drug effects*; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D006801:Humans; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D049329:Nanostructures; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*
D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D007502:Iron Chelating Agents; D011728:Pyridones; C020366:3-hydroxy-4-pyridone; D007501:Iron