Nanoparticle Delivery of Transition-Metal Chelators to the Brain: Oxidative Stress will Never See it Coming!

Abstract

The pathological lesions typical of Alzheimer disease (AD) are sites of significant and abnormal metal accumulation. Metal chelation therapy, therefore, provides a very attractive therapeutic measure for the neuronal deterioration of AD, though its institution suffers fundamental deficiencies. Namely, chelating agents, which bind to and remove excess transition metals from the body, must penetrate the blood-brain barrier (BBB) to instill any real effect on the oxidative damages caused by the presence of the metals in the brain. Despite many advances in chelation administration, however, this vital requirement remains therapeutically out of reach: the most effective chelators—i.e., those that have high affinity and specificity for transition metals like iron and copper—are bulky and hydrophilic, making it difficult to reach their physiological place of action. Moreover, small, lipophilic chelators, which can pass through the brain’s defensive wall, essentially suffer from their over-effectiveness. That is, they induce toxicity on proliferating cells by removing transition metals from vital RNA enzymes. Fortunately, research has provided a loophole. Nanoparticles, tiny, artificial or natural organic polymers, are capable of transporting metal chelating agents across the BBB regardless of their size and hydrophilicity. The compounds can thereby sufficiently ameliorate the oxidative toxicity of excess metals in an AD brain without inducing any such toxicity themselves. We here discuss the current status of nanoparticle delivery systems as they relate to AD chelation therapy and elaborate on their mechanism of action. An exciting future for AD treatment lies ahead.

Nanoparticles, Lung Injury, and the Role of Oxidant Stress

“…One example, is the potential use of nanomaterials to transport metal chelating agents to pathological sites of significant and abnormal metal accumulation within Alzheimer disease patients (132). Transition metal accumulations in Alzheimer disease brains are thought to have an important role in local oxidative reactions and pathological lesions.…”

“…Transition metal accumulations in Alzheimer disease brains are thought to have an important role in local oxidative reactions and pathological lesions. Metal-chelating agents with the assistance of nanocarriers that can cross the blood-brain barrier (regardless of their size and hydrophilicity), selectively bind, remove and “redox-silence” transition metals provide promising potential for therapeutic intervention (132). Engineered nanomaterials may be also act as targeted enhancers of oxidative stress for tumor or cancer therapy.…”

The Impact of Copper Ions on the Activity of Antibiotic Drugs

“…It was shown that the incubation of hepatocytes with Cu ions rapidly increases the production of free radicals [ 19 ]. Having in mind all the roles of copper ions in the human body, as well all the mentioned pathological conditions linked with its imbalance in the human organism, it is not surprising that the possible antimicrobial, antiviral, anti-inflammatory, and antitumor potential of copper ion metal chelators is being thoroughly studied [ 7 , 20 ].…”

Copper and cuproptosis: new therapeutic approaches for Alzheimer’s disease

“…Certain chelators for Cu are hydrophilic and require small hydrophobic molecules to cross the blood-brain barrier (BBB) (Kenche and Barnham, 2011). However, nanoparticle delivery systems could be promising and intriguing methods for metal chelation in AD treatment (Bonda et al, 2012). This novel technology has been used in multiple studies to treat different illnesses (Hernando et al, 2016;Xiao et al, 2022;Guadarrama-Escobar et al, 2023).…”