基于近红外荧光探针技术研究芥子气原型在体内的动态过程

芥子气是典型的双功能烷化剂，被称为“毒剂之王”。芥子气原型是体内发挥毒性的主要成分，明确芥子原型在体内的动态过程是芥子气研究中不可回避的重要科学问题。文献报道的芥子气原型在体内分布的数据差异较大甚至相互矛盾，究其原因是分析方法存在问题。近年来，近红外荧光探针技术逐渐成为医学和生命科学领域不可或缺的研究手段之一。申请人前期制备了三个系列的芥子气近红外荧光探针，并初步筛选出了一个性能优良的荧光探针。该探针能够快速、灵敏、高选择性的检测样本中的芥子气原型（反应时间为1.7 min，检测限为4.35 ppm）。我们拟应用芥子气荧光探针分析芥子气原型分子在体内的动态过程，构建芥子气原型在体内的时效、量效关系，明确整体动物和细胞水平上芥子气原型的蓄积方式和清除半衰期，切实回答留存时相、蓄积方式和芥子气持续毒性的相关性。上述研究对进一步阐明芥子气中毒机制、指导临床治疗和开发靶向抗毒药物均具有重大意义。

Sulfur mustard is the representative of bifunctional alkylating agent and described as “the king of toxic agent”. The toxicity of intact sulfur mustard is the mainly toxicant in organisms. It is an inevitable scientific problem that the dynamic processes of intact sulfur mustard in organisms for the mechanism of toxicity induced by sulfur mustard. As so far the data of intact sulfur mustard in organisms from the publications is varies considerably because of the issues of detection method. Recently the technique of near infrared fluorescent probe is becoming the indispensable study method. Applicant have developed three series of sulfur mustard near-infrared fluorescent probes and screened an excellent probe. The detection limits of the probe is 4.35 ppm, and the reaction time is 1.7 min. We plan that applying sulfur mustard near-infrared fluorescent probes study the dynamic processes of intact sulfur mustard in organisms by different ways of exposure. We desire to ensure the relationship between time and dose of intact sulfur mustard in organisms and the potential accumulation ways and elimination half-time of intact sulfur mustard in tissues and cells, after then response to the correlation between retention phase, accumulation pattern and persistent toxicity of sulfur mustard. The study is vital to further elucidate the toxicological mechanisms, advise the clinical treatment and develop targeted antitoxic drugs.