Immobilized phosphate receptors for the treatment of hyperphosphatemia

高磷酸盐血症是当血清中磷酸盐浓度超过1.46 mM时发生的一种病症， 常见于晚期慢性和急性肾病（CKD）和肾衰竭患者。 维持性血液透析不能清除血液中的磷酸盐;因此，几乎所有维持性血液透析患者 血液透析有高磷血症。目前的治疗主要依赖于饮食限制， 口服磷酸盐结合剂与食物或饮料一起给药，通常不足以控制 透析患者的高磷酸盐血症这种无法控制的疾病增加了发病率，主要是 由于与血管和软组织钙化相关的心血管事件。这个项目的首要目标是 是开发，优化，并转化为临床新的亲和柱，用于正常化无机 快速、安全、有选择地从血液中去除磷酸盐。我们的中心假设是我们可以达到目标 使用与树枝状多肽缀合的镧系元素络合物。我们小组的初步结果很好 这表明具有开放配位位点镧系元素络合物可以被设计成直接从 血清和血液具有高亲和力和选择性超过其他内源性离子，存在于高得多的 血清中的浓度。这些镧系元素络合物是高度稳定的，并且在血清中或当 与磷酸盐结合，作为有效的“磷酸盐海绵”。重要的是，这些复合物对 磷酸盐可以随意调节，以达到正常的血清水平，而不会有低磷酸盐血症的危险。我们将 进一步开发、优化和评估用于从血液中去除磷酸盐的原型亲和柱。的 本申请的总体目的是合成一种新的镧系元素络合物族， 对磷酸盐具有适当的亲和力，对内源性离子具有高选择性，并将它们偶联到树枝状 所提出的研究的基本原理是， 柱将能够有效和快速地从血液中去除过量的磷酸盐，而不影响平衡。 其他内源性阴离子，如碳酸氢根。与透析结合使用，这些磷酸盐亲和力 血液透析柱将能够有效地管理高磷酸盐血症。我们计划完成我们的 通过追求以下具体目标实现目标：1）开发用于选择性的新型金属络合物 从血清中螯合磷酸盐; 2）合成并表征负载于 树突状多肽，并评估其平衡血清中磷酸盐水平的能力;和3）评估其平衡血清中磷酸盐水平的能力。 的受体固定的亲和柱，以使离体和体内的血磷酸盐水平正常化， 血液透析。我们的研究意义重大，因为它旨在开发一种新技术， 治疗CKD和肾衰竭患者的高磷血症。这将改善透析患者的结局， 生活质量我们的研究是创新的，因为它将开发第一个利用镧系元素的亲和柱 用于平衡血液中磷酸盐水平的接枝到树枝状多肽上的复合物。

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.