Nanodiamond mediated delivery of pyridinium oxime antidotes to central nervous system for potential treatment of exposure to nerve agents

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Chemico-Biological Interactions Pub Date : 2025-08-16 DOI:10.1016/j.cbi.2025.111711

Denys Bondar , Olga Smirnova , Nandish M. Nagappa , Ivo Heinmaa , Ondrej Soukup , Tereza Kobrlova , Jakub Opravil , Martina Hrabinova , Daniel Jun , Pavel Starkov , Pirjo Spuul , Kamil Kuča , Vadym N. Mochalin , Yevgen Karpichev

{"title":"Nanodiamond mediated delivery of pyridinium oxime antidotes to central nervous system for potential treatment of exposure to nerve agents","authors":"Denys Bondar , Olga Smirnova , Nandish M. Nagappa , Ivo Heinmaa , Ondrej Soukup , Tereza Kobrlova , Jakub Opravil , Martina Hrabinova , Daniel Jun , Pavel Starkov , Pirjo Spuul , Kamil Kuča , Vadym N. Mochalin , Yevgen Karpichev","doi":"10.1016/j.cbi.2025.111711","DOIUrl":null,"url":null,"abstract":"<div><div>Currently available antidotes against toxic organophosphorus compounds suffer from poor permeability across the blood-brain barrier (BBB) and due to this, are limited in their ability to restore the inhibited acetylcholinesterase (AChE) in the central nervous system (CNS). We designed functionalized detonation nanodiamond nanocarrier platforms to transport quaternary oxime antidotes into CNS. We showed that the nanodiamonds with covalently attached 4-oximinopyridinium moiety, cross the layer of Madin-Darby Canine Kidney (MDCK) cells, the surrogate BBB model, and demonstrate a dose-independent reactivation <em>in vitro</em> towards human AChE inhibited by nerve agents GB and VX, and pesticide paraoxon. Confocal microscopy visualization of tight junctions and actin cytoskeleton in MDCK and Human Umbilical Vein Endothelial Cells (HUVEC) revealed temporary disruption of tight junctions at higher nanoparticle concentrations without compromising cell viability or cytoskeletal integrity. Although reactivation was modest, the nanodiamond platform showed promise for delivering quaternary oxime to the central nervous system (CNS) <em>in vitro</em>. The results reveal the potential of detonation nanodiamonds as a promising delivery platform for charged therapeutic agents to CNS aimed to enhance treatment outcomes in organophosphorus poisoning.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"420 ","pages":"Article 111711"},"PeriodicalIF":5.4000,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemico-Biological Interactions","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0009279725003412","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Currently available antidotes against toxic organophosphorus compounds suffer from poor permeability across the blood-brain barrier (BBB) and due to this, are limited in their ability to restore the inhibited acetylcholinesterase (AChE) in the central nervous system (CNS). We designed functionalized detonation nanodiamond nanocarrier platforms to transport quaternary oxime antidotes into CNS. We showed that the nanodiamonds with covalently attached 4-oximinopyridinium moiety, cross the layer of Madin-Darby Canine Kidney (MDCK) cells, the surrogate BBB model, and demonstrate a dose-independent reactivation in vitro towards human AChE inhibited by nerve agents GB and VX, and pesticide paraoxon. Confocal microscopy visualization of tight junctions and actin cytoskeleton in MDCK and Human Umbilical Vein Endothelial Cells (HUVEC) revealed temporary disruption of tight junctions at higher nanoparticle concentrations without compromising cell viability or cytoskeletal integrity. Although reactivation was modest, the nanodiamond platform showed promise for delivering quaternary oxime to the central nervous system (CNS) in vitro. The results reveal the potential of detonation nanodiamonds as a promising delivery platform for charged therapeutic agents to CNS aimed to enhance treatment outcomes in organophosphorus poisoning.

Abstract Image

查看原文本刊更多论文

纳米金刚石介导的吡啶肟解毒剂向中枢神经系统的递送用于神经毒剂暴露的潜在治疗。

目前可用的针对有毒有机磷化合物的解毒剂存在血脑屏障（BBB）渗透性差的问题，因此，它们恢复中枢神经系统（CNS）中被抑制的乙酰胆碱酯酶（AChE）的能力有限。我们设计了功能化爆轰纳米金刚石纳米载体平台，将季肟解毒剂运送到中枢神经系统。我们发现，带有共价4-氨基吡啶片段的纳米金刚石可以穿过替代血脑屏障模型的Madin-Darby犬肾（MDCK）细胞层，并在体外对神经毒剂GB和VX以及农药对氧磷抑制的人乙酰胆碱酯（AChE）表现出剂量无关的再激活。共聚焦显微镜观察MDCK和人脐静脉内皮细胞（HUVEC）的紧密连接和肌动蛋白细胞骨架显示，在更高的纳米颗粒浓度下，紧密连接会暂时中断，但不会影响细胞活力或细胞骨架的完整性。虽然再激活是适度的，但纳米金刚石平台显示出将季肟输送到体外中枢神经系统（CNS）的希望。这些结果揭示了爆轰纳米金刚石作为一种有前途的向中枢神经系统输送带电治疗剂的平台，旨在提高有机磷中毒的治疗效果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Chemico-Biological Interactions 生物-毒理学

CiteScore

7.70

自引率

3.90%

发文量

410

审稿时长

36 days

期刊介绍： Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.