Cancer Chemoradiotherapy Duo: Nano-Enabled Targeting of DNA Lesion Formation and DNA Damage Response
Cancer Chemoradiotherapy Duo: Nano-Enabled Targeting of DNA Lesion Formation and DNA Damage Response
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癌症放化疗组合：纳米靶向 DNA 病变形成和 DNA 损伤反应
DOI：
10.1021/acsami.8b10901
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发表时间：
2018-10-24
影响因子：
9.5
通讯作者：
Wang, Jun
中科院分区：
文献类型：
--
作者：
Jiang, Wei;Li, Quan;Wang, Jun
DNA损伤的产生及其修复的预防是决定放射治疗（RT）疗效的关键。然而，目前几乎所有的策略，以提高RT只集中在这两个方面之一，而忽略了他们的组合的必要性。在这项工作中，我们引入了DNA双靶向纳米医学（NM）的概念，以同时增强DNA损伤的形成和防止随后的修复。简而言之，负载在NM中的顺铂前药可以在细胞核中形成铂化DNA，使DNA更容易受到RT产生的电离辐射的影响。同时，时空共递送的伏立诺他，一种组蛋白去乙酰化酶抑制剂，抑制了双链断裂的建立，并导致细胞凋亡，这可能是由于抑制了DNA修复蛋白的表达。此外，这种纳米平台适用于荧光和磁共振成像技术，使准确贩运的NM以及可靠的实时成像引导的精确RT。最后，结果从体外和体内共同揭示，这种双重作用系统达到显着增强的辐射结果。总之，我们的成像引导DNA双靶向设计代表了一种有效的癌症精确RT的新策略。
Both production of DNA damage and subsequent prevention of its repair are crucial in concluding the therapeutic outcome of radiotherapy (RT). However, nearly all current strategies for improving RT focus only on one of the two aspects and overlook the necessity of their combinations. In this work, we introduce a concept of DNA dual-targeting nanomedicine (NM) to simultaneously enhance DNA lesion formation and prevent the succeeding repair. Briefly, the cisplatin prodrug loaded in NM can form platinated DNA in cell nuclei, making DNA more vulnerable to the ionizing radiation generated by RT. Concomitantly, the spatial-temporally codelivered vorinostat, a histone deacetylase inhibitor, prolongs the build-up of double-strand breaks and causes cell apoptosis en masse, probably due to the suppressed expression of DNA repair proteins. Furthermore, this nanoplatform is suitable for fluorescence and magnetic resonance imaging techniques, enabling accurate trafficking of the NM as well as reliable real-time imaging-guided precision RT. Finally, results from in vitro and in vivo jointly reveal that this dual action system attains a remarkably enhanced radiotherapeutic outcome. In conclusion, our imaging-guided DNA-dual-targeting design represents a novel strategy for efficient cancer precision RT.