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 DNAdual-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 dualaction 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.

Redox-sensitive iodinated polymersomes carrying histone deacetylase inhibitor as a dual-functional nano-radiosensitizer for enhanced radiotherapy of breast cancer

“…Radiotherapy (RT) is one of the most widely used and effective treatments for malignant solid tumors in clinical settings (Citrin, 2017 ; Pallares & Abergel, 2020 ; Lehrer et al., 2021 ). The anticancer effect of RT is based on DNA damage of cancer cells via high-energy photons or charged particles (Meidanchi et al., 2015 ; Jiang et al., 2018a , 2018b ; Hahn et al., 2021 ). The outcome of RT varies, however, to a great extent, because some tumor cells are resistant to RT and patients can’t tolerate high dose X-ray irradiation.…”

Nanoparticulation of Prodrug into Medicines for Cancer Therapy

“…[ 131 ] The histone deacetylases inhibitor vorinostat was co‐loaded with CPP into synthetic polymer for enhancement of DNA lesion formation and prevention of the subsequent repair at the same time. [ 132 ] The CPP was also utilized as a sacrificial electron acceptor fluorescence produced by nanoscintillators to increase the hydroxyl radicals (·OH) yield, therefore enhanced the curative effects of X‐ray‐induced‐PDT (Figure 9C ). [ 133 ] By cross‐linking with Fe 3+ ions, CPP‐polyphenol and low‐fouling PEG‐polyphenol derivatives were co‐assembled into nanocomplexes which displayed four times higher inhibition against tumor growth than cisplatin (Figure 9D ).…”

Nanotechnology-Based Histone Deacetylase Inhibitors for Cancer Therapy

“…(C) Stimuli-responsive controlled drug release: the illustration of pH-responsive DOX loading nanoparticles by the self-assembling of PBA conjugated polycaprolactone, and the drug release in response to different pH (Kularatne et al, 2018). (D) Combination therapy: the scheme of vorinostat-containing nanoparticles for sensitizing radiotherapy (Jiang et al, 2018). *p < 0.05 was considered statistically significant in all analysis (95% confidence level).…”

“…A nanomedicine for codelivery of vorinostat and cis, cis, trans-[Pt(NH3) 2 Cl 2 (OOC(CH2) 8 CH3) 2 ] was developed, which was characterized by the de-shieldable corona that reduced the capture by the RES but was removed in the acidic TME to expose the cell-penetrating peptides (Jiang et al, 2018). The cell-penetrating peptide facilitated the nanomedicine into the tumor cells and the released Pt chelated into DNA and the released vorinostat sensitized the cancer cells by promoting ROS production and inhibiting DAN repair proteins (Figure 2D).…”