Rational Design of Cancer-Targeted Selenadiazole Derivative as Efficient Radiosensitizer for Precise Cancer Therapy

Abstract

Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovery of targeted therapies for personalized cancer medicine. Herein, cancer targeting RGD peptide has been covalently conjugated to selenadiazole derivative (RGD-SeD) to improve its cancer selectivity. The RGD decoration significantly enhances the anticancer efficacy of RGD-SeD in αVβ3 integrin-overexpressing HepG2 liver cancer cells but not in normal liver cells. Cellular uptake assay and fluorescent imaging confirmed the selectivity of RGD-SeD to integrin-overexpressing cancer cells. RGD-SeD strongly sensitizes HepG2 cells to clinically used X-ray radiotherapy through ROS overproduction, which triggers DNA damage-mediated apoptosis and G2/M cell cycle arrest. This X-ray-responsive DNA damage activates p53 signaling pathways by phosphorylation of ATM/ATR and γ-H2A.X. Furthermore, in a HepG2 nude mice xenograft model, the combined treatment of RGD-SeD and X-ray demonstrates potent in vivo antitumor efficacy via induction of apoptotic cell death but shows no toxicity on the functions of major organs. In summary, this study provides a strategy to design a selenium-based cancer targeting radiosensitizer for precise cancer therapy.

Responsive Degradable Theranostic Agents Enable Controlled Selenium Delivery to Enhance Photothermal Radiotherapy and Reduce Side Effects

“…Excessive ROS generated by X‐ray irradiation may react with DNA in the nucleus and cause DNA damage. [ 30 ] DNA damage in HeLa cells of different groups was investigated. Immunofluorescence analysis indicated that the control, Se@SiO 2 , and Se@SiO 2 @Bi NCs groups had no γ ‐H2AX fluorescence signals, indicating no DNA damage (Figure 5c).…”

Enhanced Cancer Therapy by Combining Radiation and Chemical Effects Mediated by Nanocarriers

“…In the past decades, a great number of studies demonstrated that Se species are promising agents for cancer therapeutics, due to their capability of generating reactive oxygen species (ROS), which can induce apoptosis in tumor cells . Interestingly, Se‐containing compounds combined with radiotherapy appeared to specifically enhance the radiosensitivity of cancer cells resulting in a wave of selenium related publications . It needs to be mentioned that the mechanism of action of selenium is still not well‐understood.…”

“…[88,89] Interestingly, Secontaining compounds combined with radiotherapy appeared to specifically enhance the radiosensitivity of cancer cells resulting in a wave of selenium related publications. [90][91][92] It needs to be mentioned that the mechanism of action of selenium is still not well-understood. An increase in ROS levels was observed when combining Se compounds with radiotherapy, which is not necessarily only related to the production of secondary electrons, but may have a different origin.…”

<p>Effect of Chitosan Magnetic Nanoparticles Loaded with Ang2-siRNA Plasmids on the Growth of Melanoma Xenografts in Nude Mice</p>

“…During the experiment, the tumor length (L) and width (W) were measured with a Vernier caliper. The tumor volume was calculated with the formula: V= L 2 ×W 21 . The calculated results were used to plot the tumor growth curve.…”