Cancer Chemoradiotherapy Duo: Nano-Enabled Targeting of DNA Lesion Formation and DNA Damage Response

Abstract

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.