Immobilized phosphate receptors for the treatment of hyperphosphatemia

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Hyperphosphatemia, a condition that occurs when the phosphate concentration in serum exceeds 1.46 mM, is common among patients with advanced chronic and acute kidney disease (CKD) and kidney failure. Maintenance hemodialysis does not remove phosphate from blood; thus, almost all patients on maintenance hemodialysis have hyperphosphatemia. Current treatment relies primarily on dietary restrictions and the administration of oral phosphate binders with food or drink which are often insufficient to manage hyperphosphatemia for individuals on dialysis. This inability to manage the disorder increases morbidity, mostly due to cardiovascular events related to vascular and soft tissue calcification. The overarching goal of this project is to develop, optimize, and translate to the clinic novel affinity columns for normalizing the levels of inorganic phosphate from blood quickly, safely, and selectively. Our central hypothesis is that we can achieve our goal using lanthanide complexes conjugated to dendritic polypeptides. Strong preliminary results from our group indicate that lanthanide complexes with open coordination sites can be designed to bind phosphate directly from serum and blood with high affinity and selectively over other endogenous ions that are present in much higher concentrations in serum. These lanthanide complexes are highly stable and do not leach metal in serum or when bound to phosphate, working as effective `phosphate sponges'. Importantly, the affinity of these complexes for phosphate can be tuned at will so as to achieve normal serum levels without risking hypophosphatemia. We will further develop, optimize, and evaluate a prototype affinity column for the removal of phosphate from blood. The overall objective of this application is to synthesize a new family of lanthanide complexes that have an appropriate affinity for phosphate and high selectivity over endogenous ions and to conjugate them onto dendritic polypeptides The rationale for the proposed research is that lanthanide complexes immobilized on affinity columns will enable the efficient and rapid removal of excess phosphate from blood without affecting the balance of other endogenous anions such as bicarbonate. Used in conjunction with dialysis, these phosphate affinity hemodialysis columns will enable efficient management of hyperphosphatemia. We plan to accomplish our objectives by pursuing the following Specific Aims: 1) Develop novel metal complexes for the selective sequestration of phosphate from serum; 2) Synthesize and characterize lanthanide receptors supported on dendritic polypeptides and evaluate their ability to balance phosphate levels in serum; and 3) Evaluate the ability of receptor-immobilized affinity columns to normalize blood phosphate levels ex vivo and in vivo during hemodialysis. Our research is significant because it aims to develop a new technology to efficiently and safely treat hyperphosphatemia in patients with CKD and renal failure. This will improve dialysis patient outcome and quality of life. Our research is innovative because it will develop the first affinity columns utilizing lanthanide complexes grafted onto dendritic polypeptides for balancing phosphate levels in blood.