Nanoparticle and Iron Chelators as a Potential Novel Alzheimer Therapy

Abstract

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.

Gold Nanoparticles Inhibit Matrix Metalloproteases without Cytotoxicity

“…Recent reports demonstrated that PVPcoated NPs show vibrations by Fourier transform infrared spectroscopy spectra indicating the presence of C-N and carbonyl groups in the pyrrolidone ring (Borodko et al 2006;Pinkhasova et al 2012), and an overall negative charge is recorded in zeta potential measurements. In this study, the negative charge of PVPcoated NPs (AuNPs: -41.9 mV, PtNPs: -36.2 mV) ( Table) is a factor for MMP inhibition as we speculate that AuNPs or PtNPs directly chelate Zn 2+ in the MMP catalytic domain (Liu et al 2010;Tanakit et al 2012).…”

Metalloproteases/anti-metalloproteases imbalance in chronic obstructive pulmonary disease

“…As such, the dosage and the length of the treatments may be better monitored by individual intracellular zinc content. However, as recently performed in Alzheimer's disease to remove metals from the brain [83], the best results in COPD therapy might also be achieved using nanoparticles conjugated with synthetic MMP inhibitors that are directed at specific targets, such as MMPs in the lung, because the removal of zinc inactivates MMPs to nonfunctional apoenzyme [84].…”

Review of drugs for Alzheimer's disease

“…As an example, desferrioxamine, a natural iron scavenger, is a specifi c chelator with a high affi nity for aluminum, copper, and zinc. Desferrioxamine is widely used in the treatment of AD (47). However, it requires continuous dosing due to its short circulating half-life.…”