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

描述（由申请人提供）：已知暴露于镉（Cd）、铅（Pb）、汞（Hg）、铬酸盐（CrO42-）、亚砷酸盐（As） （III）和砷酸盐（AsO43-）等有毒金属会诱发各种有害人体健康的疾病。NIEHS的重点领域之一是“螯合化学的发展，可以作为治疗的基础，以改善异常的金属积累和有毒暴露的影响。”根据PA-06-181，本探索性/发展性R21提案将开发和评估新的生物相容性螯合材料，这将导致螯合化学领域的突破，特别是环境暴露后人体重金属。这项工作解决了NIEHS的一项关键任务，因为该研究所“对来自环境来源的有毒金属暴露负有主要责任”。完整的螯合疗法包括(1)螯合胃肠道液体中的金属离子，以限制摄入物质的全身吸收；(2)螯合血液中已从所有暴露途径（口服、皮肤和吸入）全身吸收的金属离子。自20世纪40年代以来，体内有毒金属固定化涉及在金属暴露后使用乙二胺-四乙酸酯（EDTA）或二巯基琥珀酸（DMSA）。然而，这些螯合剂仍然存在许多缺点和低疗效。它们也不能有效去除镉和有毒阴离子，如铬酸盐和砷酸盐。我们假设功能化二氧化硅（SAMMS）和磁性纳米颗粒，在我们的许多初步数据和出版物中都被证明是在环境清理中去除有毒金属的高效稳定的吸附剂，也可以有效地用于生物基质中用于人体的金属降解。它们将在更高的亲和力、特异性和容量方面优于目前fda批准的EDTA和DMSA。此外，我们假设这些新的螯合材料将表现出更快的去除率，更小的毒性，总的来说，它们的使用将导致更低的治疗成本。为了验证这一假设，将评估SAMMS去除胃肠道有毒金属的能力，同时评估磁性纳米颗粒体外螯合全血中有毒金属的能力。不同的有机基团将被精心设计成对目标金属具有高亲和力。对纳米材料的螯合性能、材料稳定性、蛋白质污染和细胞摄取的评估将在体外进行，使用相关的物理化学形式和适合急性和慢性人体接触有毒金属的金属浓度。还将对这两种材料进行改进，以增加其稳定性，并最大限度地减少蛋白质污染和细胞摄取。该结果将为我们在未来的R01项目中继续使用动物模型进行体内研究奠定坚实的基础。已知暴露于镉（Cd）、铅（Pb）、汞（Hg）、铬酸盐（CrO42-）、亚砷酸盐（As(III)）和砷酸盐（AsO43-）等有毒金属会诱发各种对人体健康有害的疾病。NIEHS的重点领域之一是“螯合化学的发展，可以作为治疗的基础，以改善异常的金属积累和有毒暴露的影响。”为了响应PA-06-181，本探索性R21提案将开发和评估新型生物相容性纳米材料，该材料将大大优于目前fda批准的螯合剂，从而在上述重金属螯合治疗领域取得突破。

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.