A combination of liposomal sunitinib plus liposomal irinotecan and liposome co-loaded with two drugs enhanced antitumor activity in PC12-bearing mouse

Abstract

Pheochromocytomas are highly angiogenic neuroendocrine tumors. The side effects of treatment with cytotoxic agents frequently outweigh the benefits. Neuroendocrine tumors are highly angiogenic, dependent on vascular endothelial growth factor and receptor (VEGFR) activation. Sunitinib has antitumor and antiangiogenic activities that target VEGFRs. We investigated the antitumor activity of liposomal sunitinib and irinotecan alone and in combination. Liposomal sunitinib and irinotecan, and liposomes co-loaded with both drugs were prepared, and antitumor activity and biodistribution were examined in nude mice bearing PC12 tumors. Liposomal sunitinib increased in life span (ILS, 14.3%) compared with free sunitinib (−17.1% ILS) with moderate tumor growth suppression, whereas liposomal irinotecan suppressed tumor growth significantly without a survival benefit compared with free irinotecan (−21.7 and −13.3% ILSs, respectively). The combination of liposomal sunitinib plus liposomal irinotecan, and liposomes co-loaded with both drugs, induced significant inhibition of tumor growth and increased life-span more than the combination of free drugs. Accumulation of irinotecan in tumors by the combination of the two liposomal drugs and liposomes co-loaded with both drugs was significantly increased compared with the combination of free drugs. This study provides novel formulations of sunitinib and irinotecan in combination for the treatment of pheochromocytoma.

Keywords::

• Pheochromocytoma
• combination therapy
• liposomes
• sunitinib
• irinotecan

Acknowledgments

We thank Mr. Masataka Date, Mr. Masahiro Tamai, Ms. Li Shi, and Ms. Yukimi Taniguchi for excellent technical assistance with respect to the in vivo and in vitro experiments.

Declaration of interest

This study was supported in part by the Ministry of Education, Culture, Sports, Science and Technology of Japan, by the Science Research Promotion Fund by the Promotion and Mutual Aid Corporation for Private Schools of Japan and by the Advanced research for medical products Mining Programme of the National Institute of Biomedical Innovation (NIBIO).