Advancing Kidney Nanowarming through Scaleable Coating of Iron Oxide Nanoparticles

通过可扩展的氧化铁纳米颗粒涂层促进肾脏纳米变暖

• 批准号: 10240279
• 负责人: Jacqueline L Pasek-Allen
• 金额: $ 3.77万
• 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: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240279
• 关键词: Address; American; Animal Model; Animal Organ; Binding; Biological; Cells; Chemistry; Complex; Convection; Cryopreservation; Cryoprotective Agents; Crystallization; Data; Development; Dextrans; Diagnostic Imaging; Graft Rejection; Heating; Hour; Human; Ice; Image; Immunosuppression; Kidney; Kidney Transplantation; Length; Ligands; Magnetism; Medical; Methods; Minnesota; Mus; Organ; Organ Donor; Organ Preservation; Organ Transplantation; Oryctolagus cuniculus; Patients; Perfusion; Production; Property; Protocols documentation; Quality of life; Rattus; Reporting; Research; Rewarming; Sampling; Science; Silicon Dioxide; Societies; Solubility; Starch; System; Technology; Time; Tissue Engineering; Tissue Viability; Tissues; Translating; Transplant Recipients; Transplantation; United States National Institutes of Health; Universities; Waiting Lists; base; biomaterial compatibility; cancer therapy; clinical application; cost; cost effective; design; gang; imaging properties; in vitro testing; in vivo; iron oxide; iron oxide nanoparticle; kidney preservation; mouse model; nanoparticle; nanowarming; new technology; phosphonate; preservation; radio frequency; scale up; small molecule; success

Advancing Kidney Nanowarming through Scaleable Coating of Iron Oxide Nanoparticles ABSTRACT The inability to preserve donor kidneys for more than a few hours significantly contributes to organ shortages, poor organ matching, and poor quality of life for transplant recipients. Using radiofrequency excited iron oxide nanoparticles (IONPs) dispersed in cryoprotectants (CPAs), the Bischof group at the University of Minnesota has successfully rewarmed small (< 80 mL) cryopreserved (-140 ºC) biological samples, including a rabbit kidney. To reliably produce IONPs at a scale needed to nanowarm whole human kidneys, however, a simpler, biocompatible coated IONP is needed that 1) is stable in CPAs, 2) has a low volume fraction, and 3) is inexpensive and easy to produce in batches > 1g. To address this need, we designed an easy-to-make small-molecule phosphonate linker (PLink) which contains a phosphonate “anchor” for high irreversible binding to iron oxide and a carboxyl “handle” for ligand attachment. This linker enables ligands such as PEG to bind to IONPs without complex chemistry and can be used to coat > 1g of IONPs per batch. We already have preliminary data to show that this PLink coating method preserves heating and imaging IONP properties. In order to develop this technology for use in rewarming cryopreserved kidneys, we will 1) determine PLink coating effects on heating, imaging, and biocompatibility properties of two commercially available IONPs and one lab-made IONP, and 2) scale up coated IONP production for in vivo mouse studies and ex vivo rat kidney perfusion. When we have completed these aims, we will be able to produce stable coated IONPs in bulk, which will allow us to significantly accellerate the development of actual kidney cryopreservation and nanowarming for transplantation.

通过可扩展的氧化铁纳米颗粒涂层促进肾脏纳米变暖 抽象的 无法保存供体肾脏超过几个小时，严重导致器官短缺、贫困 使用射频激发的氧化铁纳米粒子导致器官匹配和移植受者的生活质量差。 （IONP）分散在冷冻保护剂（CPA）中，明尼苏达大学的 Bischof 小组成功地 重新加热小型（< 80 mL）冷冻保存（-140 ℃）生物样品，包括兔肾，以可靠地生产。 IONP 的规模需要对整个人类肾脏进行纳米加热，然而，一种更简单、生物相容的涂层 IONP 是 需要 1) 在 CPA 中稳定，2) 体积分数低，3) 价格便宜且易于批量生产 > 1g。为了满足这一需求，我们设计了一种易于制造的小分子膦酸酯连接体（PLink）， 含有一个膦酸酯“锚”，用于与氧化铁高度不可逆地结合，以及一个用于配体的羧基“手柄” 该接头使 PEG 等配体能够与 IONP 结合，无需复杂的化学反应，并且可以 用于每批次涂覆 > 1g IONP 我们已经有初步数据表明这种 PLink 涂覆方法。 保留加热和成像 IONP 特性，以便开发该技术用于复温。 对于冷冻保存的肾脏，我们将 1) 确定 PLink 涂层对加热、成像和生物相容性的影响 两种市售 IONP 和一种实验室制造的 IONP 的特性，以及 2) 按比例放大的涂层 IONP 当我们完成这些目标时，我们就可以进行体内小鼠研究和离体大鼠肾脏灌注的生产。 将能够批量生产稳定的涂层 IONP，这将使我们能够显着加速 实际肾脏冷冻保存和移植纳米加温技术的发展。