Iron plays a pivotal role in human physiology by serving multifarious functions such as cofactor in a few enzymes, transport of hemoglobin etc.  However, its overload leads to dreadful diseases such as Alzheimer’s disease, Hemochromatosis, Aceruloplasminemia, and Transfusional Siderosis.  Iron in free form provokes the production of reactive oxygen species (ROS) via Fenton reaction.  Therefore, scavenging the excess metal is of considerable importance in biomedical field.

 
2. Chelation Therapy

Currently, chelation therapy is widely used to overcome the iron intoxication.   A few Food and Drug Administration (FDA) approved drugs currently in use show better chelation.  Desferrioxamine, Deferasirox and Deferiprone are some of the FDA approved drugs to circumvent the iron overload.  Despite the interesting metal chelation activity exerted by these chelators, their systemic toxicity, rapid elimination from systemic circulation greatly impede their success.

 
3. Nanotechnology for Chelators

To address the issues associated with low molecular weight compounds a potential polymer conjugated iron chelator, which successfully removes free iron from the cells, is of utmost importance in the Biomedical field.  Although a few nanoparticles used for metal overload diseases, studies on polymer conjugated iron chelator are significantly less [1,2]. Synthesized starch conjugated desferrioxamine which showed better chelation efficacy and entered phase 1b clinical trials several years ago. However, it has been found to induce urticarial reactions in patients and discouraged at a later date.  In another study dendrimer conjugated desferrioxamine showed significant improvement in therapeutic properties by chelating iron. In this study, initially hyperbranched glycerol scaffold was prepared and several molecules of desferrioxamine were covalently conjugated to it. Long systemic circulation of the dendrimer conjugated chelator was observed resulting in enhanced therapeutic property.  However, in HPG conjugated DFO study optimization and biodistribution of the molecules is yet to be determined.

 
Liu’s study of conjugating iron chelators to nanoparticle showed some promise in reducing the iron overload in brain tissue. They used 2-Methyl-N-(2′-aminoethyl or 3′-aminopropyl)-3-hydroxyl-4-pyridinone (MAEHP), 2-Methyl (or Ethyl)-N-(2′-hydroxyethoxy) methyl-3-hydroxyl-4-pyridinone (MHEMHP). Monodispersed polystyrene particles with carboxyl groups on the surface were used to conjugate MAEHP chelators, each of which contained a free primary amino group available for the conjugation.  These nanoparticles showed adsorption on lipoproteins such as low density lipoprotein (LDL). Since they mimic lipoproteins, they are first adsorbed on the low density lipoprotein receptors. Further they are uptaken by brain endothelial cells.  Despite the better efficacy of the low molecular weight chelators and polymeric chelators, a few limitations impede their success.  There has been an ambiguity whether polymeric chelators are mile stones in chelation therapy or a mirage.

Although development of substantial iron chelators appears ambiguous, a few further studies may open a few novel avenues.  In line with this, specific insights into conjugation of aminodiacetic acid ligands to biocompatible polymers such as poly (ethylene glycol) may significantly enhance systemic circulation, reduce toxicity and exhibit robust iron chelation.  Since aminodiacetic acid containing compounds show better chelation efficacy, they can be used to develop potential armamentarium for iron overload diseases.

1. Philip E, Hallaway (1989) Proc Natl Acad. Sci. USA 86: 10108-10112.

2. Obulesu (2016) Curr Drug Metab 17:142-149.