Combined therapeutic efficacy of 188Re-liposomes and sorafenib in an experimental colorectal cancer liver metastasis model by intrasplenic injection of C26-luc murine colon cancer cells

摘要

Rhenium-188 (¹⁸⁸Re) displays abundant intermediate energy β emission and possesses a physical half-life of 16.9 h. Sorafenib is an orally available multikinase inhibitor that targets Raf kinases and vascular endothelial growth factor receptors (VEGFRs). Sorafenib has demonstrated preclinical and clinical activity against several types of tumors, such as renal cell and colorectal carcinoma. In this study, we investigated the efficacy of radiotherapeutics of ¹⁸⁸Re-liposomes combined with sorafenib in a C26-luc metastatic colorectal liver tumour mouse model. Liver metastases were established by intrasplenic injection of C26-luc murine colon cancer cells. Based on the results of the toxicity assessment, an administration dose of 80% the maximum tolerated dose was selected. ¹⁸⁸Re-liposomes were administered on day 1, when metastases of several hundred micrometers in diameter were observed. In the combination therapy group, 10 mg/kg sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar) was administered every other day for 1 week and the survival of mice was assessed. The tumor growth was more significantly inhibited in the ¹⁸⁸Re-liposome plus sorafenib group compared with the ¹⁸⁸Re-liposome alone, sorafenib alone and untreated normal saline groups (P=0.0000). Furthermore, ¹⁸⁸Re-liposomes combined with sorafenib achieved higher survival rates compared with the ¹⁸⁸Re-liposome alone, sorafenib alone and untreated normal saline groups (P=0.0000). These results support the use of combined radio-chemotherapy with ¹⁸⁸Re-liposomes plus sorafenib as a viable treatment option in the adjuvant setting for liver metastases of colorectal cancer.