Iron Chelation and Nanoparticle Target Delivery in the Development of New Multifunctional disease-modifying Drugs for Alzheimer‘s Disease

Keywords::

• Alzheimer‘s disease
• iron chelator
• metals
• multifunctional disease-modifying therapeutic
• nanoparticle
• neurodegeneration
• oxidative stress
• target delivery

The current situation of Alzheimer‘s disease (AD) management is deeply disappointing because there is no way to prevent or cure the disease, and the medicines on the market are only able to provide moderate symptomatic delay. It is also very frustrating that the mechanisms underlying AD‘s evolution remain largely unknown and the pace of developing disease-modifying drugs (DMDs) is extremely slow. According to the Alzheimer‘s Association, an estimated 5.4 million Americans have this progressive, degenerative and irreversible brain disorder, and the number will exponentially increase if no new therapeutic approaches are developed. The disease has also put a huge economic burden on society with an annual cost of approximately US$180 billion for patient care in the USA alone. Obviously, there is an urgent and unmet need for rapidly developing new therapeutics for AD.

In recent years, growing evidence indicates that iron accumulation in the brain plays an important role in AD onset and progression [1] and, therefore, iron-chelation agents have been suggested as new potential DMDs for the neuronal deterioration of AD [2,3]. However, some obstacles concerning chelators‘ toxic side effects and bioavailability, such as brain targeting and blood–brain barrier (BBB) penetration, have hindered further investigation both in the understanding of the pathophysiological role of iron in AD and in the evaluation of the efficacy and safety of chelation therapy [4]. In fact, target delivery of iron-chelation drugs opens a new arena for both further exploiting the insight of iron action in AD and for rapidly discovering new DMDs for the disease. Among other useful drug-delivery approaches, nanoparticles serving as vehicles to transport therapeutics have become attractive for various disease treatments. In this article, the rationales and current status of developing iron-chelator–nanoparticle delivery systems as potential DMDs for AD have been presented. In addition, a brief perspective of this development has been provided.

The role of iron in AD & chelation therapy for the disease

Iron is an essential element in the normal human aging process that can generate harmful free radicals, causing oxidative damage to all classes of biological molecules [5]. Indeed, the sites of significant and abnormal iron accumulation, which can act as redox-active centers, have been found in the pathological lesions of AD – senile plaques (SP) and neurofibrillary tangles (NFT) [1]. Thus, as a consequence, the concentrations of damaged mitochondrial DNA, proteins and phospholipids by oxidation have been demonstrated to be significantly higher in AD than in control cases [3]. In addition, studies also suggest that iron accumulation can accelerate the build-up of SP and NFT in AD and make them more neurotoxic [6]. Interestingly, MRI studies suggest higher iron concentrations in the brains of AD populations than of healthy controls, and the pathological role of brain iron in AD patients help to further connect the dots between imbalanced iron and disease [7].

With the emergence of pathological and epidemiological evidence linking dysregulated brain iron and AD, iron-chelation therapy has become an attractive therapeutic measure for the disease. Significantly, besides chelating iron, chelation therapy is also able to target multiple pathological pathways that are believed to lead to the complex neurodegeneration of AD [8–10]. Studies have shown that chelation agents can serve as multifunctional DMDs by providing at least a three-pronged mode of action to prevent and treat AD [11]. First, since redox-active iron is able to catalyze harmful free radical generation and thereby lead to oxidative stress, which can initiate and promote neurodegeneration of AD, chelation therapies that selectively bind, remove and/or ‘redox silence‘ iron have been suggested as a useful therapeutic strategy for the disease. Some chelation agents also have the ability to scavenge free radicals, thus mitigating free radical-caused damage in AD. Second, iron ions are considered to be able to aggravate the self-assembly and neurotoxicity of amyloid β (Aβ) as mentioned above. Therefore, it is not surprising that such chelation agents can markedly attenuate Aβ toxicity, and blocking Aβ aggregation by chelation provides a valuable therapeutic approach. Third, since some oxidative stress, resulting from iron-mediated processes is associated with increased Aβ, which is a consequence of the coordinated upregulation of β- and γ-secretases and Aβ protein precursor (AβPP), not surprisingly, treatment of AβPP-overexpressing transgenic mice (an AD model with significant Aβ deposition and oxidative stress) with chelation agents results in less Aβ deposition.

Indeed, both experimental and clinical studies have shown promising results with chelation treatment for AD [4]. Desferrioxamine, ethylenediaminetetraacetic acid and iodochlorhydroxyquin (clioquinol) have been studied with AD patients, and these chelation treatments have shown significant clinical improvement [12–15]. However, concerns have been raised over the BBB penetration of the chelators and/or potential toxic side effects [2,4]. For example, desferrioxamine, an iron chelator approved by the US FDA for iron-overload treatment, is unable to penetrate the BBB because of its hydrophilic nature and possesses serious side effects (e.g., neurotoxicity and neurological changes). Ethylenediaminetetraacetic acid is also a FDA-approved chelation drug with hydrophilic character and shows the same lack of BBB penetration. While some lipophilic chelators with small molecular weights, such as bi- or tri-dentate iron chelators, have the capability of penetrating the BBB; they may have considerable neurotoxicity and lack the ability to deplete iron in the brain despite effectively binding iron, which can result in additional toxicity in the brain. Although the lipophilic clioquinol is able to enter the brain, its use has now had to be stopped in consideration of its serious toxicity. Great efforts have also been taken to develop safer, more effective and targeted chelation therapeutics [2,6–9]; however, there is no clear-cut solution for their clinical application so far. Thus, the use of chelators as multifunctional DMDs for further studies on AD treatment is currently limited and still remains challenging.

Targeted nanoparticle delivery of iron chelators as new therapeutics for AD

Although a large body of studies supports chelation therapy as a potential multifunctional therapeutic approach to prevent and treat AD, the difficulties presented by strong iron binding, bidirectional crossing of BBB and the potential toxicity of the currently available chelators hamper further studies. However, these obstacles may be overcome by utilizing nanoparticle-delivery technology, which has shown promise in brain targeting, improved drug efficacy and reduced drug toxicity [16]. For example, a recent study using nanoparticles to deliver rivastigmine, a drug for the treatment of AD, has shown increased brain concentration of the drug in an animal model [17]. A key mechanism by which nanoparticles are able to cross the BBB is that they can mimic low-density lipoprotein and thereby enable themselves to interact with the low-density lipoprotein receptors, resulting in their uptake by brain endothelial cells [3,16].

Indeed, utilizing nanoparticle–iron chelator delivery technology, our studies have indicated that nanoparticles covalently conjugated to iron chelators have the potential to deliver the chelators into the brain without altering iron-chelating capability. In addition, the chelators‘ toxicity can be limited by their conjugation with nanoparticles [2,11]. Most importantly, the chelator–nanoparticles can bring the chelator–iron complexes out of the brain, thus rooting out the excess iron toxicity [2,18]. All of these can tremendously improve the safety profile and effectiveness of this new chelation therapeutic approach compared with iron chelators alone. Furthermore, it is also very interesting that our studies show that chelator–nanoparticles have the potential to act as multifunctional DMDs with respect to excess metal depletion, oxidative damage inhibition, Aβ aggregation and toxicity prevention [2,11]. This novel approach could lead to the discovery of new, safer and more effective iron-chelation therapeutics that can target multiple etiologies in AD. We believe that further development would provide profound impact on AD prevention and treatment, as well as other neurodegenerative diseases, such as amyotrophic lateral sclerosis, Friedreich‘s ataxia, and Huntington‘s and Parkinson‘s disease. This kind of chelation agent may also be applied to the development of new neuroimaging pharmaceuticals for neurological diseases‘ diagnosis.

Future perspective

Despite the mounting scientific evidence that strongly supports the role of redox-active iron in oxidative stress cascades that lead to pathologies of AD, including SP and NFT, controversy still remains regarding whether the dysregulated iron is the cause or a consequence of the disease and, as a result, whether the iron-chelation therapy holds merit for AD management. Nevertheless, the development of better targeting iron-chelation agents with tolerable toxicity and sufficient efficacy will not only provide a valuable tool for further understanding the AD pathogenesis, but may also lead to new approaches to prevent, treat and even cure the disease. In addition, since increased levels of several other metals (e.g., copper and zinc) in AD are suggested as important contributors to AD, such chelation agents can also be utilized for these metals‘ role investigation and possible AD management [4]. This is because a chelation agent, regardless of synthetic or natural origin, may have high affinity for one metal ion, but chelate other metals. Although this phenomenon in many circumstances is considered an undesirable effect on chelation therapy, in the case of AD, affinity for iron, copper and zinc may pose useful rather than detrimental effects, since these metal ions are simultaneously elevated and implicated as oxidative instigators, which may in fact be the ‘Achilles‘ heel‘ of AD, providing an unique opportunity for chelation therapy [4]. Obviously, there is a great opportunity to further exploit new safer, more effective iron-chelation therapeutic agents with better brain-targeting ability, because the current chelation drugs and drug candidates are far from satisfying for AD management. Although progress has been made in the development of such ideal chelation agents, such as nanoparticle-delivered iron chelators, challenges still remain; for example, improving the targeting ability of the chelator–nanoparticle systems to the brain and limiting their passive accumulation into the liver and other peripheral organs. In addition, concerns remain over the toxicity of the chelator–nanoparticle systems and further study is needed. There is a huge platform to extend our knowledge of and exploit new therapeutic approaches for AD and, no doubt, many difficulties and challenges are ahead. Persistent collaborative efforts from multidiscipline experts with open minds will help fulfill the ultimate goals to rapidly discover new multifunctional DMDs to prevent, treat and cure this devastative disease.

Financial & competing interests disclosure

The authors thank the NIH (5R01NS52677 to Gang Liu), the NIH RCMI Center for Interdisciplinary Health Research (GI2-RR013646 to George Perry) and the Alzheimer‘s Association for their financial support. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.