The principal aim of this Phase I grant is to develop a device with immobilized chelator of clinical capacity, for removal of excess iron from patients with iron overload. We have developed such a device, using polysulfon hollow fiber cartridges with immobilized chelators, for aluminum chelation in dialysis patients. Preliminary studies using this chelating device indicate that iron removal by such methodology is feasible. Other preliminary studies done in dogs using cartridges with immobilized desferrioxamine showed that iron could be removed rapidly by such techniques. In Phase I, we plan to develop several types of immobilized chelators. Using activated agarose as a macromolecular support, we will immobilize some new oral chelators (EHPG, PIH) and alpha-aminoacyl hydroxamate, a chelator ligand with high iron affinity. We will prepare a series of carboxymethyl-dextrans with increase content of acid gropus for the binding of large amounts of the desferrioxamine for iron chelators. We will then measure iron binding capacity of each of the above chelating agents in batch experiments. Iron depletion by each of the chelators will be measured using saline solution with albumin which contains various concentrations of iron, between 50 and 500 mcg/dL. The strength of iron binding will be estimated by the eluted amount of iron by water soluble chelators, such as EDTA. Chelators that look promising in the batch experiments will be immobilized onto hollow fiber cartridges. Cartridges for immobilization will be those marked for hemodialysis with high ultrafiltration performance. Each cartridge contains about 12,000, asymmetric poly-sulfon hollow fibers consisting of a thin capillary membrane surrounded by a relative thick, macroporous shell which imparts mechanical strength to the membrane and serves as a support to the chelating agent which is deposited in the macropores and at the outside wall of the fibers. The nominal pore size of the membrane is less than 30 kilodaltons, and allows iron and other metals to pass through. Hollow fiber cartridges with the immobilized chelators will then be tested. Using aqueous solutions of iron, the device will be tested for kinetics of iron removal and iron binding capacity. Using blood from hemodialysis patients having iron overload, the devices will be tested for kinetics of iron removal. Identification of the sources of iron 0 removed will be explored by measuring iron in individual serum fractions separated by HPLC in recirculating blood. These Phase I studies will test the feasibility of this approach to iron chelation and identify the final chelator for the prototype to be developed in Phase II.Awardee's statement of the potential commercial applications of the research:A device with immobilized iron chelator that eliminates the side effects of chelation therapy, will benefit patients who require monthly blood transfusions, and chelation for iron overload. The number of patients involved (nalassemia: 5,000 in U.S.A., 300,000 worldwide; sickle cell disease, post-stroke: 30,000; hemodialysis: 24,000, etc.) and the yearly number of cartridges needed for ongoing chelation, make the device commercially attractive. Two companies are interested in its commercial development.National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
