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

基本信息

批准号：
10681398
负责人：
Valerie C. Pierre
金额：
$ 40.15万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
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/10681398
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 Safety Serum Site Structure Technology Translating Water calcification compliance behavior design dietary restriction improved in vivo innovation inorganic phosphate metal complex new technology novel pill polypeptide prototype receptor soft tissue

项目摘要

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。常见于患有晚期慢性和急性肾病（CKD）和肾衰竭的患者。维持性血液透析不会去除血液中的磷酸盐；因此，几乎所有接受维持治疗的患者血液透析有高磷血症。目前的治疗主要依靠饮食限制和将口服磷酸盐结合剂与食物或饮料一起给药，这通常不足以管理透析患者的高磷血症。这种无法控制疾病的情况会增加发病率，主要是由于与血管和软组织钙化相关的心血管事件。该项目的总体目标是开发、优化并转化为临床新型亲和柱，以标准化无机物水平快速、安全、选择性地从血液中去除磷酸盐。我们的中心假设是我们能够实现我们的目标使用与树突状多肽缀合的镧系元素络合物。我们小组的初步成果强劲表明具有开放配位位点的镧系元素络合物可以设计为直接结合磷酸盐与存在于高得多的其他内源性离子相比，血清和血液具有高亲和力和选择性血清中的浓度。这些镧系元素络合物高度稳定，不会在血清中或当与磷酸盐结合，起到有效的“磷酸盐海绵”的作用。重要的是，这些复合物的亲和力磷酸盐可以随意调节，以达到正常的血清水平，而不会出现低磷血症的风险。我们将进一步开发、优化和评估用于去除血液中磷酸盐的原型亲和柱。这该应用的总体目标是合成一个新的镧系元素配合物家族，该配合物具有对磷酸盐有适当的亲和力，对内源离子具有高选择性，并将它们缀合到树突上所提出的研究的基本原理是通过亲和力固定化镧系元素络合物柱将能够有效、快速地去除血液中多余的磷酸盐，而不影响平衡其他内源性阴离子，例如碳酸氢根。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管理高磷血症。我们计划完成我们的通过追求以下具体目标来实现目标： 1）开发新型金属配合物，用于选择性从血清中封存磷酸盐； 2) 合成并表征镧系元素受体树突状多肽并评估其平衡血清中磷酸盐水平的能力； 3）评估能力受体固定化亲和柱使离体和体内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，以高效、安全地治疗 CKD 和肾功能衰竭患者的高磷血症。这将改善透析患者的治疗效果生活质量。我们的研究具有创新性，因为它将开发出第一个利用镧系元素的亲和柱接枝到树突状多肽上的复合物用于平衡血液中的磷酸盐水平。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Walk Across the Lanthanide Series: Trend in Affinity for Phosphate and Stability of Lanthanide Receptors from La(III) to Lu(III).

穿越镧系元素系列：从 La(III) 到 Lu(III) 的稀土受体对磷酸盐的亲和力和稳定性的趋势。

DOI：
发表时间：
2021-10-18
期刊：
影响因子：
4.6
作者：
Wilharm, Randall K;Huang, Sheng;Gugger, Isabel J;Pierre, Valérie C
通讯作者：
Pierre, Valérie C

Design Principles and Applications of Selective Lanthanide-Based Receptors for Inorganic Phosphate.

无机磷酸盐选择性镧系受体的设计原理和应用。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Pierre, Valérie C;Wilharm, Randall K
通讯作者：
Wilharm, Randall K

Achieving Selectivity for Phosphate over Pyrophosphate in Ethanol with Iron(III)-Based Fluorescent Probes.

使用铁 (III) 基荧光探针实现乙醇中磷酸盐相对于焦磷酸盐的选择性。

DOI：
发表时间：
2022-07-25
期刊：
影响因子：
8
作者：
Huang, Sheng;Pierre, Valérie C
通讯作者：
Pierre, Valérie C

Luminescent lanthanide probes for cations and anions: Promises, compromises, and caveats.

用于阳离子和阴离子的发光镧系元素探针：承诺、妥协和警告。

DOI：
10.1016/j.cbpa.2023.102374
发表时间：
2023-07-28
期刊：
Current opinion in chemical biology
影响因子：
7.8
作者：
Thibaut L. M. Martinon;V. Pierre
通讯作者：
V. Pierre

Exploiting the Fluxionality of Lanthanide Complexes in the Design of Paramagnetic Fluorine Probes.

在顺磁氟探针设计中利用镧系元素络合物的通量性。

DOI：
10.1021/acs.inorgchem.1c03908
发表时间：
2022-03-07
期刊：
Inorganic chemistry
影响因子：
4.6
作者：
Wilharm RK;Ramakrishnam Raju MV;Hoefler JC;Platas-Iglesias C;Pierre VC
通讯作者：
Pierre VC

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Valerie C. Pierre其他文献

Phosphonate coating of commercial iron oxide nanoparticles for nanowarming cryopreserved samples

DOI：
10.1039/d1tb02483c
发表时间：
2022-04
期刊：
Journal of Materials Chemistry B
影响因子：
7
作者：
Jacqueline L. Pasek-Allen;Randall K. Wilharm;Zhe Gao;Valerie C. Pierre;John C. Bischof
通讯作者：
John C. Bischof