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共价性亲体-分子剂药物结合纳米剂用于近距离启用反应性疗法

Wenhui Gao¹, Xiaoyuan Yang¹, Qingrong Li¹

¹School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai, 200240, China.

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

|January 17, 2025

概括

这项研究引入了一种使用硫化物交换 (SuFEx) 点击化学的新型共价药物合物,用于不可逆转地与癌细胞结合. 这种有针对性的方法与非共价方法相比,显著增强了瘤抑制.

科学领域:

药用化学医学化学
纳米技术纳米技术
在瘤学瘤学.

背景情况:

点击化学反应,特别是硫交换 (SuFEx),在生理条件下提供高效的反应性.
由于其生物相容性和效率,SuFEx反应对于构建共价蛋白药物非常有价值.
有针对性的药物输送系统对于提高治疗效率和最大限度地减少癌症治疗中的非目标效应至关重要.

研究的目的:

开发一种新型的共价附体-分子剂药物结合纳米剂,利用近距离启用的SuFEx反应.
调查纳米剂对向蛋白质的不可逆转的结合能力,特别是人类表皮生长因子受体2 (HER2).
在HER2阳性癌症模型中评估共价纳米剂的体内抗瘤疗效.

主要方法:

将潜在的生物反应性非自然氨基酸,硫酸-L-氨酸 (FSY) 引入附属体支架 (Z_HER2:342-Cys).
修改后的附体与分子剂药物 (CR8) 的结合,形成一个两性结合物.
结合物的自我组装成附体-药物结合纳米剂 (ADCN) 和通过SuFEx反应与癌细胞上的HER2对其共价结合的评估.

主要成果:

开发的Z_HER2:342-36_FSY-CR8 ADCN证明了与HER2的特定结合,并通过近距离启用的SuFEx反应形成了共价键.
联结合模式导致永久的目标参与,增加了瘤部位的药物度.
在HER2阳性卵巢瘤模型中,共价ADCN实现了90.03%的显著瘤抑制比率,超过了非共价对应物 (64.25%).

结论:

这项研究成功地证明了SuFEx点击化学的潜力,用于创建具有增强向性和有效性的共价药物合物.
开发的共价附体-药物结合纳米剂通过确保不可逆转的药物结合,为改善癌症治疗提供了一个有希望的策略.
这种方法对设计下一代具有卓越抗瘤活性的向癌症疗法具有重大意义.

关键词:

在SuFEx反应中,附体-分子粘剂药物联合体协价纳米剂是一种共价纳米剂.可靠的近距离反应疗法.

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