Immobilized phosphate receptors for the treatment of hyperphosphatemia

高磷血症，当血清中的磷酸盐浓度超过1.46 mM时发生的一种情况 在晚期慢性和急性肾脏疾病(CKD)和肾功能衰竭患者中常见。 维持性血液透析不会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和 口服磷酸盐粘合剂与通常不足以管理的食物或饮料一起给药 透析患者的高磷血症。这种无法管理疾病的能力增加了发病率，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、优化并转化为临床的新型亲和柱，以使无机元素水平正常化 快速、安全、有选择性地从血液中提取磷酸盐。我们的中心假设是我们可以实现我们的目标 使用与树枝状多肽连接的稀土络合物。我们小组取得了强劲的初步结果 表明具有开放配位的稀土络合物可以被设计成直接结合磷酸盐 血清和血液具有高亲和力，并选择性地超过其他存在于高得多的 血清中的浓度。这些稀土络合物非常稳定，不会在血清中或在 结合磷酸盐，起到有效的“磷酸盐海绵”的作用。重要的是，这些络合物对 磷酸盐可以随意调节，以达到正常的血清水平，而不会有低磷血症的风险。我们会 进一步开发、优化和评估用于从血液中去除磷酸盐的亲和柱原型。这个 本申请的总体目标是合成一类新的具有 合适的磷酸盐亲和力和对内源离子的高选择性，并将它们连接到树枝状结构上 多肽拟议研究的基本原理是稀土络合物固定在亲和力上 柱子将能够有效和快速地从血液中去除多余的磷，而不会影响平衡 其他内源性阴离子，如重碳酸盐。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血症。我们计划完成我们的 目标通过追求以下具体目标：1)开发新的金属络合物用于选择性 从血清中分离磷酸盐；2)合成和表征负载于 树突状多肽及其平衡血清磷酸盐水平的能力；以及3)评估其能力 用受体固定化亲和层析柱使体内和体外血磷水平正常化 血液透析。我们的研究具有重要意义，因为它旨在开发一种高效和安全的新技术 治疗慢性肾脏病合并肾功能衰竭患者的高磷血症。这将改善透析患者的预后，并 生活质量。我们的研究具有创新性，因为它将开发出第一个利用稀土元素的亲和色谱柱 将复合体嫁接到树突状多肽上，以平衡血液中的磷酸盐水平。

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.