Self-targeting platinum(IV) amphiphilic prodrug nano-assembly as radiosensitizer for synergistic and safe chemoradiotherapy of hepatocellular carcinoma.

Chemoradiotherapy is a widely used treatment for patients with malignancies such as hepatocellular carcinoma (HCC). However, it remains challenging to realize safe and synergistic chemotherapy and radiation sensitization. Herein, we design a self-targeting nano-assembly (STNA) based on platinum(IV)-lactose amphiphilic prodrug for synergistic and safe chemoradiotherapy of HCC. The Pt STNA would improve the tumor accumulation due to the targeting ability of lactose to HCC cells. After receptor-mediated endocytosis, Pt STNA would release cisplatin(II) in cancer cells to form DNA-binding, thus inducing DNA damage and cell apoptosis. Meanwhile, the DNA-binding also causes cell cycle arrest in the radiation-sensitive G2/M phase by the up-regulation of phosphorylated checkpoint kinase 1 (p-Chk1) expression. Furthermore, under X-ray irradiation, Pt STNA as radiosensitizer possesses a strong X-ray attenuation ability to deposit more energy, thus elevating the level of reactive oxygen species (ROS) to amplify the cell-killing effect of radiotherapy in the G2/M phase with increased DNA damage. As a result, Pt STNA exhibits significant synergistic therapeutic effects in chemoradiotherapy with no adverse effects in vitro and in vivo. Overall, we present a novel self-targeting nano-assembly strategy based on widely used Pt drugs for synergistic chemotherapy and radiation sensitization of HCC treatment.