Novel Chelators for Highly Efficient Removal of Toxic Heavy Metals in Humans

高效去除人体有毒重金属的新型螯合剂

• 批准号: 7388677
• 负责人: Wassana Yantasee
• 金额: $ 26.75万
• 依托单位: BATTELLE PACIFIC NORTHWEST LABORATORIES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388677
• 关键词: Acute; Address; Adverse effects; Affinity; Animal Model; Anions; Area; Arsenates; Arsenites; Beds; Benign; Binding; Biocompatible; Biological; Blood; Blood Pressure; Breathing; Cadmium; Calcium; Cations; Cells; Cessation of life; Charge; Chelating Agents; Chelation Therapy; Chemistry; Chromates; Chronic; Class; Complex; Condition; DMSA; Data; Dermal; Development; Devices; Disadvantaged; Disease; Dose; Environmental Exposure; Ethylenediamine; Ethylenediamines; Excision; Excretory function; Exhibits; Exposure to; Filtration; Foundations; Future; Gastrointestinal tract structure; Goals; Health; Heavy Metals; Hemodialysis; Human; Immobilization; In Vitro; Institutes; Intake; Intravenous; Ions; Iron; Kidney Failure; Laboratories; Lead; Liquid substance; Magnesium; Magnetism; Materials Testing; Membrane; Mercury; Metal exposure; Metals; Minerals; Mission; Nephrotoxic; Nuclear; Oral; Pacific Northwest; Particle Size; Performance; Physical Chemistry; Plasma; Proteins; Publications; Rate; Rivers; Route; Silicon Dioxide; Solid; Source; Specificity; Stomach; Stomach Content; Surface; System; Tablets; Technology; Testing; Time; Toxic effect; Toxicant exposure; Treatment Cost; United States; United States Food and Drug Administration; Water; Whole Blood; Work; Zinc; absorption; capsule; cell injury; cellular imaging; chelation; cost; design; exposed human population; gastrointestinal; improved; in vivo; iron oxide; magnetic field; metal poisoning; monolayer; nanomaterials; nanoparticle; novel; physical property; prevent; response; size; toxic metal; uptake

DESCRIPTION (provided by applicant): Exposure to toxic metals like cadmium (Cd), lead (Pb), mercury (Hg), chromate (CrO42-), arsenite (As) (III), and arsenate (AsO43-) are known to induce various diseases that are detrimental to human health. One of NIEHS emphasis areas is the development of "Chelation chemistry that can serve as the foundation for therapies to ameliorate aberrant metal accumulations and the effects of toxic exposures." In response to PA-06-181, this Exploratory/Developmental R21 proposal will develop and evaluate novel biocompatible chelating materials that will lead to a breakthrough in the field of chelation chemistry, specifically for heavy metals in humans after environmental exposure. This work addresses a key mission of NIEHS since the institute "has primary responsibility with respect to toxic metal exposure from environmental sources." Complete chelation therapies encompass (1) chelating the metal ions in the gastrointestinal fluids in order to limit systemic absorption of ingested materials and (2) chelating the metal ions in blood that have been absorbed systemically from all routes of exposure (oral, dermal and inhalation). Since the 1940s, in vivo toxic metal immobilization has involved the use of ethylenediamine-tetraacetate (EDTA) or dimercaptosuccinic acid (DMSA) following metal exposures. However, these chelation agents still have many disadvantages and low efficacy. They are also not effective in removing Cd and toxic anions such as chromate and arsenate. We hypothesize that functionalized silica (SAMMS) and magnetic nanoparticles, both proven in our numerous preliminary data and publications to be highly efficient and stable sorbents for removal of toxic metals in environmental cleanups, can also be used effectively in biological matrices for metal decorporation in humans. They will be better than the currently FDA-approved EDTA and DMSA in terms of higher affinity, specificity and capacity. In addition, we hypothesize that these new chelating materials will exhibit a faster removal rate, less toxicity, and overall their use will result in lower costs of treatment. To test the hypothesis, SAMMS will be evaluated for toxic metal removal from gastrointestinal (GI) tract while magnetic nanoparticles will be evaluated for extracorporeal chelation of toxic metals from whole blood. Differing organic groups will be carefully designed to have a high affinity for the target metals. Assessment of chelating performance, material stability, protein fouling, and cell uptake of the nanomaterials will be done in vitro using relevant physicochemical forms and concentrations of the metals appropriate to acute and chronic human exposure of the toxic metals. Refinement of both materials to increase their stability as well as minimize protein fouling and cell uptake will also be performed. The results will form a strong foundation for our continued effort with in vivo studies using animal models in a future R01 project. Exposure to toxic metals like cadmium (Cd), lead (Pb), mercury (Hg), chromate (CrO42-), arsenite (As(III)), and arsenate (AsO43-) are known to induce various diseases that are detrimental to human health. One of NIEHS emphasis areas is the development of "Chelation chemistry that can serve as the foundation for therapies to ameliorate aberrant metal accumulations and the effects of toxic exposures." In response to PA-06-181, this exploratory R21 proposal will develop and evaluate novel biocompatible nanomaterials that will lead to a breakthrough in the field of chelation therapies of the above heavy metals by substantially outperforming the current FDA-approved chelating agents.

描述（由申请人提供）：暴露于诸如镉（CD），铅（PB），汞（HG），铬酸盐（CRO42-），砷矿（AS）（III）和砷酸盐（ASO43-）等有毒金属中诱导各种不利于人类健康的疾病。 NIEHS的重点之一是发展“可以作为改善异常金属积累及其毒性暴露作用的疗法的基础的发展。”为了响应PA-06-181，该探索性/发育R21提案将开发和评估新型的生物相容性螯合材料，这将导致螯合化学领域的突破，特别是在环境暴露后针对人类重金属的突破。这项工作涉及NIEHS的主要任务，因为该研究所“在环境来源的有毒金属暴露方面负有主要责任”。完整的螯合疗法包括（1）螯合胃肠道液体中的金属离子，以限制摄入的材料的全身吸收，（2）（2）在所有暴露途径（口服，皮肤和吸入途径）中系统地吸收的血液中的金属离子）。自1940年代以来，在金属暴露后，体内有毒金属固定化涉及使用乙二胺 - 四乙酸乙酸乙酯（EDTA）或dimercaptosonconic酸（DMSA）。但是，这些螯合剂仍然具有许多缺点和低功效。它们也无效去除CD和有毒阴离子（例如铬酸盐和砷）。我们假设功能化的二氧化硅（SAMM）和磁性纳米颗粒在我们的众多初步数据和出版物中证明是高效且稳定的吸附剂，可在环境清理中去除有毒金属，也可以在人类的生物学中有效地用于人类的生物学装饰。 。就更高的亲和力，特异性和能力而言，它们将比当前批准的EDTA和DMSA更好。此外，我们假设这些新的螯合材料将表现出更快的去除率，较小的毒性，并且总体使用它们的使用将导致治疗成本较低。为了检验该假设，将评估SAMMS从胃肠道（GI）中去除有毒金属，同时将评估磁性纳米颗粒的磁性纳米颗粒，以便从全血中对毒性金属的体外螯合。不同的有机基团将经过精心设计，以对目标金属具有高亲和力。将在体外评估螯合性能，材料稳定性，蛋白质结垢和纳米材料的细胞摄取，并使用相关的物理化学形式和适合急性和慢性人类对有毒金属暴露的金属的浓度进行体外进行。还将进行两种材料以提高其稳定性，以及最小化蛋白质结垢和细胞摄取的细化。结果将为我们在未来的R01项目中使用动物模型进行体内研究的持续努力构成坚实的基础。已知暴露于镉（CD），铅（PB），汞（HG），铬酸盐（CRO42-），砷矿（AS（III））和砷酸盐（ASO43-）等有毒金属。人类健康。 NIEHS的重点之一是发展“可以作为改善异常金属积累及其毒性暴露作用的疗法的基础的开发”。为了响应PA-06-181，该探索性R21提案将开发和评估新颖的生物相容性纳米材料，这将在上述重金属的螯合疗法领域取得突破，从而实质上优于当前FDA批准的螯合剂。