Cisplatin under oriented external electric fields: A deeper insight into electrochemotherapy at the molecular level

Electrochemotherapy is an effective strategy for the treatment of solid tumors by exposing tumor cells to electric fields to enhance the bioactivity of non‐permeable or low permeable anticancer drugs, such as cisplatin. To understand the improved efficiency of cisplatin in the electrochemotherapy, the effects of oriented external electric fields (OEEFs) on the geometric structure and relevant electronic properties of cisplatin have been systemically investigated by density functional theory (DFT) computations in this work. Our results reveal that the presence of selective OEEFs on cisplatin can not only weaken its Pt‐Cl bonds, but also enhance the intramolecular charge transfer in it, which effectively accelerates the critical hydrolysis step involved in the mechanism of biological activity for this drug. Moreover, the chosen OEEFs can facilitate the attack of the singly aquated cis‐[Pt(NH3)2(H2O)Cl]+ on DNA, and enlarge the water solubility of cisplatin and its aquated product. These OEEF‐induced geometric and electronic modifications can indeed help to improve the antitumor activity of cisplatin, which provides a deeper insight into the higher efficacy of electrochemotherapy than traditional chemotherapy from a molecular point of view. Cisplatin under electric fields: A deeper insight into electrochemotherapy is provided by theoretically investigating the effects of oriented external electric fields on the geometric structures and relevant electronic properties of cisplatin based on the density functional theory.