复旦大学步文博团队报道了碳自由基(R·)灭活NF-κB用于根治性封顶治疗。相关研究成果于2024年4月29日发表于国际一流学术期刊《德国应用化学》。

灭活过度活化的转录因子可以克服肿瘤治疗耐药性，但其不可治愈的特性限制了传统抑制剂的发展。

该文中，研究人员报道了以碳为中心的自由基（R·），可以通过封端NF-κB和DNA中的活性位点来灭活NF-κB的转录。研究人员构建了一种热敏R引发剂负载的两亲性纳米胶束，以促进R的细胞内递送。在43°C的温度下，产生的R向核苷酸碱基中的双键进行亲电自由基加成，同时通过自由基链式反应覆盖NF-κB中的巯基残基。

结果，NF-κB核转位和NF-κB-DNA结合都受到抑制，导致高达94.1%的显著NF-κB抑制。研究人员在临床射频消融肿瘤治疗模型中进一步应用了R胶束，显示出显著的NF-κB失活，从而抑制了肿瘤转移。

根治性封端策略不仅为解决临床肿瘤热疗中的热沉效应提供了一种方法，而且为癌症治疗中生物大分子的可控修饰提供了一个新的视角。

附：英文原文

Title: Carbon Free Radical (R·) Inactivates NF-κB for Radical Capping Therapy

Author: Peiran Zhao, Huiyan Li, Bingxia Sun, Chaochao Wang, Guanglei Lv, Chao Chen, Leilei Ying, Xinhong He, Dayong Jin, Wenbo Bu

Issue&Volume: 2024-04-29

Abstract: Inactivating hyperactivated transcription factors can overcome tumor therapy resistance, but their undruggable features limit the development of conventional inhibitors. Here, we report that carbon-centered free radicals (R) can inactivate NF-κB transcription by capping the active sites in both NF-κB and DNA. We construct a type of thermosensitive R initiator loaded amphiphilic nano-micelles to facilitate intracellular delivery of R. At a temperature of 43°C, the generated R engage in electrophilic radical addition towards double bonds in nucleotide bases, and simultaneously cap the sulfhydryl residues in NF-κB through radical chain reaction. As a result, both NF-κB nuclear translocation and NF-κB-DNA binding are suppressed, leading to a remarkable NF-κB inhibition of up to 94.1%. We have further applied R micelles in a clinical radiofrequency ablation tumor therapy model, showing remarkable NF-κB inactivation and consequently tumor metastasis inhibition. Radical capping strategy not only provides a method to solve the heat-sink effect in clinic tumor hyperthermia, but also suggests a new perspective for controllable modification of biomacromolecules in cancer therapy.

DOI: 10.1002/anie.202405913

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202405913