The Properties of Therapeutically Useful Iron Chelators

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

“…Notably, while these agents have slowed the progression of AD in some cases [30, 31], they are severely limited in their effectiveness due to fundamental aspects of their biochemistry. The hexadentate iron chelator Desferrioxamine (DFO), for example, which tightly binds iron(III) and moderately binds aluminum, zinc, and copper (Figure 1A, B) [31–34], has impeded the progression of AD in clinical trials, despite its high molecular weight and hydrophillicity [35–37]. Its clearance of transition metals from the brain is the proposed mechanism for its effectiveness, and indeed, it is one of two iron chelators approved by the FDA for iron overload disease [29].…”

“…Smaller metal chelation compounds, on the other hand, typically have the ability to penetrate the BBB, but are toxic upon administration [37]. In particular, bi- or tri-dentate iron chelators (those that utilize two or three atoms in their substrate-ligand bonds, respectively), such as the α-ketohydroxypyridone derivatives, efficiently bind to and remove iron from intracellular pools; however, in doing so, they eliminate much of the supply of iron necessary for the functioning of human ribonucleotide reductase—a vital enzyme necessary for the reduction of ribonucleotides to deoxyribonucleotides, and thus for DNA synthesis and cell proliferation [37, 40–44].…”

“…In particular, bi- or tri-dentate iron chelators (those that utilize two or three atoms in their substrate-ligand bonds, respectively), such as the α-ketohydroxypyridone derivatives, efficiently bind to and remove iron from intracellular pools; however, in doing so, they eliminate much of the supply of iron necessary for the functioning of human ribonucleotide reductase—a vital enzyme necessary for the reduction of ribonucleotides to deoxyribonucleotides, and thus for DNA synthesis and cell proliferation [37, 40–44]. Furthermore, due to their lipophilicity and small size, such compounds are also thought to penetrate the interior of the large ribonucleotide reductase complexes to chelate and remove the transition metal within them [45].…”

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

“…Most bi- or tridentate iron chelators with small molecular weight and high lipophilicity have the ability to penetrate the BBB, but show toxicity [108]. On the other hand, hexadentate iron chelators are considered better candidates for chelation therapy than bi- and tridentate ones because of their lower toxicity before and after chelation [108], but they have difficulty penetrating the BBB [102,108,109] due to their hydrophilicity and relative high molecular weight. One strategy to increase the BBB penetration is by enhancing the lipophilicity and lowering the molecular weight of the iron chelators, but this is believed to increase toxicity [110].…”

“…7). This is significant, as hexadentate iron chelators possess many advantages including kinetic stability, concentration independence of iron affinity, and low toxicity [108]. In addition, attempts to convert bi- or tridentate iron chelators into hexadentate chelators with various backbones suffer mainly from decreased bioavailability and the risk of potential toxicity.…”