? ? The goals of this initial research are to develop and test novel iron-chelatorman particle systems for removing excess metals (iron, aluminium, and others) from the brains of Alzheimer's disease (AD) patients and to lay the groundwork for further development of these systems in iron chelation: therapy. Although strong evidence (McLachlan et al., Lancet 337:1304.8, 1991) has shown that iron chelation can benefit AD patients by depleting excess metals from body, problems with toxicity, route of administration and restricted ability of the iron chelators to cross the BBB, have impeded the further development of this approach, We hypothesize that these impediments may be overcome by conjugating iron chelators to nanoparticles, which may serve as a vehicle to carry the chelators into the brain and bring iron-chelator complexes out using low density lipoprotein (LDL) transport mechanisms. Moreover, the brain targeting ability of the systems may increase the efficacy of excess metal depletion and hence lower potential toxicity and difficulty of administration, This pilot study will focus on synthesizing iron chelators and conjugating them with nanoparticles by covalently bonding. Also, the potential of the chelator nanoparticle systems to target the brain and cross the brain-blood barrier (BBB) will be determined by protein absorption pattern using 2-D gel technology. More important, an in vivo study using Alzheimer transgenic mice treated with these systems will be performed and thereby provide the insight in whether the systems can cross the BBB, bring iron out of the brain and protect against oxidative damage in the brain. These can be detected by using histochemical, ICP-MS, and immunochemical analyses. These mice are suited well to serve as a model in this study because of increased iron and oxidative damage levels in their brain. The same increases have already been found in the brain of the patients with Alzheimer's disease. We believe that the use of nanoparticles as a brain targeting vehicle may provide the possibility of iron chelation therapy for AD and this study may lay the groundwork for further development of iron chelator nanoparticle systems in iron chelation therapy. Moreover, this investigation may also provide some insights into iron chelation treatment for some other neurodegenerative diseases, such as Parkinson's disease and Friedreich's ataxia as well as:other: iron overload mediated diseases. Overall, this: exploratory: study may open the door for the use of iron chelator nanoparticle systems to target diseased organs for iron chelation therapy. ? ?
| Liu, Gang; Men, Ping; Kenner, Gerry H et al. (2004) Acyclonucleoside iron chelators of 1-(2-hydroxyethoxy)methyl-2-alkyl-3-hydroxy-4-pyridinones: potential oral iron chelation therapeutics. Nucleosides Nucleotides Nucleic Acids 23:599-611 |
