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构建基于谷胱甘肽响应和二氧化硅的纳米复合材料，用于螯合剂二巯基丁二酸的控制释放。

Construction of a Glutathione-Responsive and Silica-Based Nanocomposite for Controlled Release of Chelator Dimercaptosuccinic Acid.

机构信息

College of Pharmacy, Institutes of Environment and Medicine, Henan University, Kaifeng 475004, China.

Institute of Medicinal Biotechnology of Medical Science & Peking Union Medical College, Beijing 100850, China.

出版信息

Int J Mol Sci. 2018 Nov 28;19(12):3790. doi: 10.3390/ijms19123790.

DOI:10.3390/ijms19123790
PMID:30487433
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6321213/
Abstract

Dimercaptosuccinic acid (DMSA) is an oral heavy metal chelator. Although DMSA is the most acceptable chelator in the urinary excretion of toxic elements from children and adults, its defects in plasma binding and the membrane permeability limit its interaction with intracellular elements and affect its efficacy in chelation therapy. Herein, a novel nanocomposite composed of mesoporous silica nanoparticles (MSNs), disulfide bond, and DMSA was synthesized and characterized with a scanning/transmission electron microscope, IR and Raman spectra, and TGA analysis. The in vitro interactions with glutathione (GSH) and cellular uptake assays showed that it was able to be stable in extracellular environments such as in blood, be internalized by cells, and release DMSA inside via GSH-triggered disulfide cleavage reaction. The in vitro adsorption assays showed that MSNs-SH as its intracellular metabolite had strong adsorbability for models of Hg or Pb. The hemolysis and cell viability assays showed that it was compatible with blood and cells even at a concentration of 1000 μg·mL. All above could not only enable it to be a GSH-responsive drug delivery system (DDS) for DMSA delivery but also to be a solution for its defects and efficacy. Thus, introduction of intelligent DDS might open a new avenue for DMSA-based chelation therapy.

摘要

二巯丁二酸（DMSA）是一种口服重金属螯合剂。尽管 DMSA 是儿童和成人从尿液中排出有毒元素最可接受的螯合剂，但它在血浆结合和膜通透性方面的缺陷限制了其与细胞内元素的相互作用，并影响其螯合治疗的效果。在此，合成并表征了一种由介孔硅纳米粒子（MSNs）、二硫键和 DMSA 组成的新型纳米复合材料，采用扫描/透射电子显微镜、IR 和拉曼光谱以及 TGA 分析。与谷胱甘肽（GSH）的体外相互作用和细胞摄取实验表明，它能够在血液等细胞外环境中稳定存在，被细胞内化，并通过 GSH 触发的二硫键断裂反应在细胞内释放 DMSA。体外吸附实验表明，作为其细胞内代谢物的 MSNs-SH 对 Hg 或 Pb 模型具有很强的吸附能力。溶血和细胞活力实验表明，即使在 1000μg·mL 的浓度下，它也与血液和细胞相容。所有这些不仅使它能够成为一种用于 DMSA 递送的 GSH 响应型药物递送系统（DDS），还解决了其缺陷和疗效问题。因此，引入智能 DDS 可能为基于 DMSA 的螯合治疗开辟新途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e07f/6321213/f2980846d4a4/ijms-19-03790-g011.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e07f/6321213/7a24f7a7f6be/ijms-19-03790-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e07f/6321213/5670f465cc59/ijms-19-03790-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e07f/6321213/48ece8fd154e/ijms-19-03790-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e07f/6321213/1d8ef22ad3ea/ijms-19-03790-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e07f/6321213/4bcad5af9248/ijms-19-03790-g003.jpg
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