光热试剂为轴向配体的铂(Ⅳ)前药合成与克服耐药性研究

doi:10.3969/j.issn.1000-1565.2026.03.010

摘要/Abstract

摘要： 为克服抗肿瘤药物顺铂的毒副作用和耐药性,采用Pt^Ⅳ前药和光热治疗(photothermal therapy,PTT)等策略,合成了一种光热试剂Cy为轴向配体的抗肿瘤前药Pt^Ⅳ-Cy.采用分光光度法探究Pt^Ⅳ-Cy在血清中的稳定性; 采用光热成像法探究其光热性质;以A549、A549R和BRL-3A细胞为模型,采用MTT法测定其体外抗肿瘤活性;以耐药性荷瘤小鼠为模型对其体内抗肿瘤活性进行评价;采用ICP-MS、荧光显微镜成像、Western blot和免疫组化染色法探究Pt^Ⅳ-Cy的克服耐药性机制.结果表明:Pt^Ⅳ-Cy在血清中表现出优异的稳定性,在808 nm激光照射下可实现化疗和PTT的协同,对A549R的IC₅₀值降低0.85倍,而对BRL-3A细胞的IC₅₀值提高2.1倍,在提高抗肿瘤活性的同时,降低了对正常细胞的毒副作用;PTT产生的高热降低了线粒体膜电位,引起线粒体功能紊乱,抑制了MRP1蛋白的表达,提高了肿瘤细胞对铂的摄取量,通过多途径来克服耐药性.

关键词: Pt^Ⅳ前药, 光热试剂, 光热治疗, 毒副作用, 顺铂耐药性

Abstract: To overcome the toxic side effects and drug resistance of anticancer drugs cisplatin, strategies including Pt^Ⅳ prodrugs and photothermal therapy(PTT)were adopted. An antitumor prodrug Pt^Ⅳ-Cy was synthesized, using a photothermal reagent Cy served as the axial ligand.The stability of the prodrug in serum was investigated by spectrophotometry, and its photothermal properties were studied by photothermal imaging.In vitro antitumor activity was determined by the MTT assay using A549, A549R and BRL-3A cells as the models.In vivo antitumor activity was evaluated by indicators such as tumor volume and tumor weight in drug-resistant tumor-bearing mice.The mechanism of overcoming drug resistance was explored by ICP-MS, fluorescence microscopy, Western blot and immunohistochemical- 引用格式:张文恺,杨术明,马永龙,等.基于EDEM的牧场推料机器人参数优化设计与试验［J］.河北大学学报(自然科学版),2026,46(3):225-236.引用格式:王梦悦,高甲欣,王书香.光热试剂为轴向配体的铂(Ⅳ)前药合成与克服耐药性研究［J］.河北大学学报(自然科学版),2026,46(3):318-326.DOI:10.3969/j.issn.1000-1565.2026.03.010光热试剂为轴向配体的铂(Ⅳ)前药合成与克服耐药性研究王梦悦,高甲欣,王书香(河北大学化学与材料科学学院,药物化学与分子诊断教育部重点实验室,河北保定 071000)摘要:为克服抗肿瘤药物顺铂的毒副作用和耐药性,采用Pt^Ⅳ前药和光热治疗(photothermal therapy,PTT)等策略,合成了一种光热试剂Cy为轴向配体的抗肿瘤前药Pt^Ⅳ-Cy.采用分光光度法探究Pt^Ⅳ-Cy在血清中的稳定性; 采用光热成像法探究其光热性质;以A549、A549R和BRL-3A细胞为模型,采用MTT法测定其体外抗肿瘤活性;以耐药性荷瘤小鼠为模型对其体内抗肿瘤活性进行评价;采用ICP-MS、荧光显微镜成像、Western blot和免疫组化染色法探究Pt^Ⅳ-Cy的克服耐药性机制.结果表明:Pt^Ⅳ-Cy在血清中表现出优异的稳定性,在808 nm激光照射下可实现化疗和PTT的协同,对A549R的IC₅₀值降低0.85倍,而对BRL-3A细胞的IC₅₀值提高2.1倍,在提高抗肿瘤活性的同时,降低了对正常细胞的毒副作用;PTT产生的高热降低了线粒体膜电位,引起线粒体功能紊乱,抑制了MRP1蛋白的表达,提高了肿瘤细胞对铂的摄取量,通过多途径来克服耐药性.关键词:Pt^Ⅳ前药;光热试剂;光热治疗;毒副作用;顺铂耐药性中图分类号:TP242.3 文献标志码:A 文章编号:1000-1565(2026)03-0318-09DOI:10.3969/j.issn.1000-1565.2026.03.010Synthesis of a platinum(Ⅳ)prodrug with photothermal reagent as the axial ligand for overcoming drug resistanceWANG Mengyue, GAO Jiaxin, WANG Shuxiang(Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, College of Chemistry and Materials Science, Hebei University, Baoding 071000, China)Abstract: To overcome the toxic side effects and drug resistance of anticancer drugs cisplatin, strategies including Pt^Ⅳ prodrugs and photothermal therapy(PTT)were adopted. An antitumor prodrug Pt^Ⅳ-Cy was synthesized, using a photothermal reagent Cy served as the axial ligand.The stability of the prodrug in serum was investigated by spectrophotometry, and its photothermal properties were studied by photothermal imaging.In vitro antitumor activity was determined by the MTT assay using A549, A549R and BRL-3A cells as the models.In vivo antitumor activity was evaluated by indicators such as tumor volume and tumor weight in drug-resistant tumor-bearing mice.The mechanism of overcoming drug resistance was explored by ICP-MS, fluorescence microscopy, Western blot and immunohistochemical- 收稿日期:2026-01-20;修回日期:2026-02-15 基金项目:国家自然科学基金项目(22177026) 第一作者:王梦悦(1998—),女,河北大学在读硕士研究生,主要从事抗肿瘤药物方向研究.E-mail:3036193854@qq.com 通信作者:王书香(1965—),男,河北大学教授,博士,博士生导师,主要从事抗肿瘤药物方向研究.E-mail:wsx@hbu.edu.cn 第3期王梦悦等:光热试剂为轴向配体的铂(Ⅳ)前药合成与克服耐药性研究河北大学学报(自然科学版) 第46卷staining.The results showed that Pt^Ⅳ-Cy exhibited excellent stability in serum and achieved the synergism of chemotherapy and PTT under 808 nm irradiation.The IC₅₀ value against A549R cells was decreased by 0.85-fold, while that against BRL-3A cells was increased by 2.1-fold, exhibiting enhanced antitumor activity and reduced toxic side effects on normal cells.The hyperthermia of PTT decreased mitochondrial membrane potential, induced mitochondrial dysfunction, inhibited the expression of MRP1 protein, increased the uptake of platinum by tumor cells, and thus overcame drug resistance through multiple pathways.

Key words: Pt^Ⅳ prodrug, photothermal reagent, photothermal therapy, toxic side effect, cisplatin resistance

中图分类号:

TP242.3

王梦悦,高甲欣,王书香. 光热试剂为轴向配体的铂(Ⅳ)前药合成与克服耐药性研究[J]. 河北大学学报(自然科学版), 2026, 46(3): 318-326.

WANG Mengyue, GAO Jiaxin, WANG Shuxiang. Synthesis of a platinum(Ⅳ)prodrug with photothermal reagent as the axial ligand for overcoming drug resistance[J]. Journal of Hebei University(Natural Science Edition), 2026, 46(3): 318-326.

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