期刊
BIOMATERIALS
卷 289, 期 -, 页码 -出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2022.121793
关键词
Platinum amphiphilic prodrug; Self -targeting; Radiosensitizer; Chemoradiotherapy; Hepatocellular carcinoma
资金
- National Natural Science Foundation of China
- Guangdong Basic and Applied Basic Research Foundation
- Guangzhou Science and Technology Bureau
- Guangdong Science and Technology Department
- Key R & D Pro- gram of Guangdong Province
- [82171997]
- [51903119]
- [22275081]
- [2020B1515020027]
- [2021B1515120065]
- [202002020070]
- [202102010181]
- [202102010007]
- [202206010068]
- [2020B1212060018]
- [2020B1212030004]
- [2022B0303020001]
This study presents a self-targeting nano-assembly strategy based on platinum(IV)-lactose amphiphilic prodrug for synergistic and safe chemoradiotherapy of hepatocellular carcinoma (HCC). The nano-assembly targets HCC cells and releases cisplatin to induce DNA damage and cell apoptosis. Under X-ray irradiation, the assembly enhances the cell-killing effect of radiotherapy.
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.
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