Nanoparticle and iron chelators as a potential novel Alzheimer therapy.
Current therapies for Alzheimer disease (AD) such as the acetylcholinesterase inhibitors and the latest NMDA receptor inhibitor, Namenda, provide moderate symptomatic delay at various stages of the disease, but do not arrest the disease progression or bring in meaningful remission. New approaches to the disease management are urgently needed. Although the etiology of AD is largely unknown, oxidative damage mediated by metals is likely a significant contributor since metals such as iron, aluminum, zinc, and copper are dysregulated and/or increased in AD brain tissue and create a pro-oxidative environment. This role of metal ion-induced free radical formation in AD makes chelation therapy an attractive means of dampening the oxidative stress burden in neurons. The chelator desferrioxamine, FDA approved for iron overload, has shown some benefit in AD, but like many chelators, it has a host of adverse effects and substantial obstacles for tissue-specific targeting. Other chelators are under development and have shown various strengths and weaknesses. Here, we propose a novel system of chelation therapy through the use of nanoparticles. Nanoparticles conjugated to chelators show unique ability to cross the blood-brain barrier (BBB), chelate metals, and exit through the BBB with their corresponding complexed metal ions. This method may provide a safer and more effective means of reducing the metal load in neural tissue, thus attenuating the harmful effects of oxidative damage and its sequelae. Experimental procedures are presented in this chapter.
Liu
Gang
G
Department of Radiology, University of Utah, Salt Lake City, Utah, USA.
Men
Ping
P
Perry
George
G
Smith
Mark A
MA
D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015913:Chelation Therapy / Q000379:methods*; D000077588:Deferasirox; D003676:Deferoxamine / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005293:Ferritins / Q000737:chemistry; D006801:Humans; D007501:Iron / Q000737:chemistry; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008670:Metals / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
D001565:Benzoates; D004337:Drug Carriers; D007502:Iron Chelating Agents; D008670:Metals; D014230:Triazoles; D005293:Ferritins; D007501:Iron; D003676:Deferoxamine; D000077588:Deferasirox