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

描述(由申请人提供)：已知接触有毒金属如镉(Cd)、铅(Pb)、汞(Hg)、铬酸盐(CrO42-)、亚砷酸盐(As)(III)和砷酸盐(AsO43-)会引发各种危害人类健康的疾病。NIEHS的重点领域之一是“螯合化学的发展，它可以作为治疗方法的基础，以改善异常的金属堆积和中毒暴露的影响。”作为对PA-06-181的响应，这项探索性/开发性R21提案将开发和评估新型生物兼容螯合材料，这些材料将导致螯合化学领域的突破，特别是对环境暴露后人体中的重金属。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)螯合胃肠液中的金属离子，以限制摄入物质的全身吸收；(2)螯合从所有暴露途径(口腔、皮肤和吸入)中全身吸收的血液中的金属离子。自20世纪40年代以来，体内有毒金属固定化涉及到在金属暴露后使用乙二胺-四乙酸酯(EDTA)或二硫代丁二酸(DMSA)。然而，这些螯合剂仍有许多缺点，效果较低。它们也不能有效地去除镉和有毒阴离子，如铬酸盐和砷酸盐。我们推测，功能化二氧化硅(SAMs)和磁性纳米颗粒在我们大量的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和稳定的吸附剂，也可以有效地用于人体金属去孔化的生物基质中。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速度，更少的毒性，总体上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从胃肠道(GI)中清除有毒金属的情况，同时评估磁性纳米颗粒对全血中有毒金属的体外螯合作用。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。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，使用适合人类急性和慢性接触有毒金属的相关物理化学形式和浓度的金属。还将对这两种材料进行精炼，以增加其稳定性，并将蛋白质污染和细胞摄取降至最低。这一结果将为我们在未来的R01项目中使用动物模型进行活体研究奠定坚实的基础。已知接触有毒金属如镉(Cd)、铅(Pb)、汞(Hg)、铬酸盐(CrO42-)、亚砷酸盐(As(III))和砷酸盐(AsO43-)会诱发各种危害人类健康的疾病。NIEHS的重点领域之一是“螯合化学的发展，它可以作为治疗方法的基础，以改善异常的金属堆积和中毒暴露的影响。”作为对PA-06-181的响应，这项探索性的R21提案将开发和评估新型生物兼容纳米材料，通过大幅超过目前FDA批准的螯合剂，在上述重金属的螯合疗法领域取得突破。

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.