Nanoparticles for the Treatment of A lzheimer's Disease: Theoretical Rationale, Present Status and Future Perspectives

Perry³

et al. 2009

J Nanoneurosci

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Alzheimer's disease (AD) is a devastating neuro-degenerative disorder characterized by the progressive and irreversible loss of memory followed by complete dementia. Despite the disease's high prevalence and great economic and social burden, an explicative etiology or viable cure is not available. Great effort has been made to better understand the disease's pathogenesis, and to develop more effective therapeutic agents. However, success is greatly hampered by the presence of the bloodbrain barrier that limits a large number of potential therapeutics from entering the brain. Nanoparticlemediated drug delivery is one of the few valuable tools for overcoming this impediment and its application as a potential AD treatment shows promise. In this review, the current studies on nanoparticle delivery of chelation agents as possible therapeutics for AD are discussed because several metals are found excessive in the AD brain and may play a role in the disease development. Specifically, a novel approach involving transport of iron chelation agents into and out of the brain by nanoparticles is highlighted. This approach may provide a safer and more effective means of simultaneously reducing several toxic metals in the AD brain. It may also provide insights into the mechanisms of AD pathophysiology, and prove useful in treating other iron-associated neurodegenerative diseases such as Friedreich's ataxia, Parkinson's disease, Huntington's disease and Hallervorden-Spatz Syndrome. It is important to note that the use of nanoparticle-mediated transport to facilitate toxicant excretion from diseased sites in the body may advance nanoparticle technology, which is currently focused on targeted drug delivery for disease prevention and treatment. The application of nanoparticle-mediated drug transport in the treatment of AD is at its very early stages of development and, therefore, more studies are warranted.

Section: Nanoparticles As a Vehicle To Transport Iron Chelators Anmentioning

confidence: 99%

Metal Chelators Coupled with Nanoparticles as Potential Therapeutic Agents for Alzheimer's Disease

Perry³

et al. 2009

J Nanoneurosci

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“…A prototype nanoparticle-chelator conjugate (Nano-N2PY) was synthesized according to earlier studies (Figure 1) [31, 32]. Briefly, carboxylic functionalized polystyrene nanoparticles (240 nm diameter; Bangs Laboratories, Indiana) were activated by N-cyclohexyl-N’-(2-morpholinoethyl)carbodiimide methyl-p-toluensulfonate (CMC) and then reacted with the iron chelator, 2-methyl-N-(2’-aminoethyl)-3-hydroxyl-4-pyridinone (MAEHP) in 2-(N-morpholino)ethane sulfonic acid buffer solution (MES).…”

Section: Introductionmentioning

confidence: 99%

“…Freshly prepared solution of Fe(NO 3 ) 3 was incubated with Nano-N2PY [31, 32], the particles washed thoroughly with EDTA solution (5 mM), and stained with Perl’s method [47]. The particles changed from white to blue, indicating the presence of iron.…”

Section: Introductionmentioning

confidence: 99%

Nanoparticle–chelator conjugates as inhibitors of amyloid-β aggregation and neurotoxicity: A novel therapeutic approach for Alzheimer disease

Kudo

et al. 2009

Neuroscience Letters

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134

Oxidative stress and amyloid-β are considered major etiological and pathological factors in the initiation and promotion of neurodegeneration in Alzheimer disease (AD). Insomuch as causes of such oxidative stress, transition metals, such as iron and copper, which are found in high concentrations in the brains of AD patients and accumulate specifically in the pathological lesions, are viewed as key contributors to the altered redox state. Likewise, the aggregation and toxicity of amyloid-β is dependent upon transition metals. As such, chelating agents that selectively bind to and remove and/or "redox silence" transition metals have long been considered an attractive therapeutic target for AD. However, the blood-brain barrier and neurotoxicity of many traditional metal chelators has limited their utility in AD or other neurodegenerative disorders. To circumvent this, we previously suggested that nanoparticles conjugated to iron chelators may have the potential to deliver chelators into the brain and overcome such issues as chelator bioavailability and toxic side-effects. In this study, we synthesized a prototype nanoparticle-chelator conjugate (Nano-N2PY) and demonstrated its ability to protect human cortical neurons from amyloid-β-associated oxidative toxicity. Furthermore, Nano-N2PY nanoparticle-chelator conjugates effectively inhibited amyloid-β aggregate formation. Overall, this study indicates that Nano-N2PY, or other nanoparticles conjugated to metal chelators, may provide a novel therapeutic strategy for AD and other neurodegenerative diseases associated with excess transition metals.

“…8.5), which depends on the chelator chemical structures and concentrations used (80, 103). This method also provides a useful tool to screen potential chelators for mobilization of iron from the AD brain.…”

mentioning

confidence: 99%

“…This phenomenon greatly improved the metal binding stability and lowered toxicity associated with metal–chelator complexes. DFO still retains its hexadentate iron binding property after conjugation to particles (103). …”

mentioning

confidence: 99%

Nanoparticle and Iron Chelators as a Potential Novel Alzheimer Therapy

Methods in Molecular Biology

Perry

et al. 2009

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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.