Immobilized phosphate receptors for the treatment of hyperphosphatemia

用于治疗高磷血症的固定化磷酸盐受体

• 批准号: 10264064
• 负责人: Valerie C. Pierre
• 金额: $ 33.05万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10264064
• 关键词: Acute; Affect; Affinity; Anions; Bicarbonates; Binding; Blood; Blood Vessels; Cardiovascular system; Cations; Chlorides; Chronic; Chronic Kidney Failure; Clinic; Complex; Dendrimers; Dialysis patients; Dialysis procedure; Disease Management; Ensure; Equilibrium; Event; Excision; Family; Food; Geometry; Goals; Health; Hemodialysis; Hypophosphatemia; Immobilization; Individual; Ions; Kidney Diseases; Kidney Failure; Kinetics; Lanthanoid Series Elements; Link; Maintenance; Metals; Modeling; Morbidity - disease rate; Oral; Oral Administration; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Polymers; Porifera; Property; Public Health; Quality of life; Rattus; Research; Risk; Safety; Serum; Site; Structure; Technology; Translating; Water; base; calcification; compliance behavior; design; dietary restriction; improved; in vivo; innovation; inorganic phosphate; metal complex; new technology; novel; pill; polypeptide; prototype; receptor; soft tissue

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.

高磷酸血症，这种情况是在血清中的磷酸盐浓度超过1.46 mm时发生的。 在晚期慢性和急性肾脏疾病（CKD）和肾衰竭患者中常见。 维持血液透析不会从血液中去除磷酸盐。因此，几乎所有维护患者 血液透析患有高磷酸血症。当前的治疗主要依赖于饮食限制和 用食物或饮料管理口服磷酸盐粘合剂，这些粘合剂通常不足以管理 透析个体的高磷酸血症。这种无法控制这种疾病会增加发病率，主要是 由于与血管和软组织钙化有关的心血管事件。该项目的总体目标 正在开发，优化和转化为临床新型亲和力柱，以使无机水平归一化 快速，安全，有选择地从血液中磷酸盐。我们的中心假设是我们可以实现我们的目标 使用与树突状多肽结合的灯笼材料复合物。我们小组的强大初步结果 表明具有开放协调位点的灯笼型复合物可以设计为直接结合磷酸盐 血清和血液具有高亲和力，并且有选择性地比其他内源性离子有选择性 血清中的浓度。这些灯笼材料配合物高度稳定，不会在血清中浸出金属或 与磷酸盐结合，作为有效的“磷酸海绵”起作用。重要的是，这些复合物对 可以随意调整磷酸盐，以达到正常的血清水平，而不会冒降低血清。我们将 进一步开发，优化和评估原型亲和力柱从血液中去除磷酸盐。这 该应用程序的总体目的是合成一个具有新的兰烷化综合体系列 适合磷酸盐和对内源离子的高选择性的适当亲和力，并将它们偶联到树突状态 多肽的拟议研究基本原理是固定在亲和力上 列将使多余的磷酸盐从血液中有效，快速去除，而不会影响平衡 其他内源性阴离子，例如碳酸氢盐。这些磷酸盐亲和力与透析结合使用 血液透析柱将有效地管理高磷酸血症。我们计划完成我们的 通过追求以下特定目的目标：1）为选择性开发新颖的金属络合物 血清中磷酸盐的隔离； 2）合成并表征支持的灯笼受体 树突状的多肽并评估其平衡血清中磷酸盐水平的能力； 3）评估能力 在受体弹性的亲和力柱的范围 血液透析。我们的研究之所以重要，是因为它旨在开发一种新技术，以有效，安全 治疗CKD和肾衰竭患者的高磷酸血症。这将改善透析患者的结果和 生活质量。我们的研究具有创新性，因为它将开发使用灯笼的第一个亲和力列 接枝到树突多肽上，以平衡血液中的磷酸盐水平。