Necrosis targeted combinational theragnostic approach using radioiodinated Sennidin A in rodent tumor models.

Yun Ji,Yue Li,Xiao Jiang,Zhijun Fang,Meng Gao,Zhiqi Yin,Xiaoning Wang,Jian Zhang,Qingqing Wang,Yicheng Ni,Xueli Zhang,Wei Liu,Junhu Wang,Cuihua Jiang,Nan Yao,Ziping Sun

doi:10.18632/oncotarget.1728

Abstract

Residual cancer cells and subsequent tumor relapse is an obstacle for curative cancer treatment. Tumor necrosis therapy (TNT) has recently been developed to cause residual tumor regression or destruction. Here, we exploited the avidity of the sennidin A (SA) tracer and radioiodinated SA (¹³¹I-SA) to necrotic tumors in order to further empower TNT. We showed high uptake and prolonged retention of SA in necrotic tumors and a quick clearance in other non-targeted tissues including the liver. On SPECT-CT images, tumor mass appeared persistently as a hotspot. Based on the prominent targetability of ¹³¹I-SA to the tumor necrosis, we designed a combinational theragnostic modality. The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) was used to cause massive tumor necrosis, which formed the target of ¹³¹I-SA that subsequently killed the residual tumor cells by cross-fire irradiation of beta particles. Consequently, ¹³¹I-SA combined with CA4P significantly inhibited tumor growth, extended tumor doubling time and prolonged mean animal survival. In conclusion, ¹³¹I-SA in combination with necrosis inducing drugs/therapies may generate synergetic tumoricidal effects on solid malignancies by means of primary debulking and secondary cleansing process.

Highlights

Cancer remains a major cause of human suffering and death worldwide
Based on the underlying principle that radiation can be delivered in a targeted way by attaching a certain radionuclide to a molecule or antibody, which selectively accumulates in tumor necrosis and emits radiation to kill and/or restrain www.impactjournals.com/oncotarget adjacent residual cancer cells
We further investigated the anticancer efficacy and safety of 131I-sennidin A (SA) as a radiopharmaceutical in combination with a vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) in mice with subcutaneous S180 tumor

Summary

Introduction

Cancer remains a major cause of human suffering and death worldwide. New developments of radiotherapy and chemotherapy have made the progress in cancer treatment [1, 2], but cancer cure is still difficult to achieve except for the early radical surgery. The main reason is, after the above therapies, the presence of residual cancer cells and subsequent tumor recurrence and metastasis, which forms a hindrance for clinical and experimental oncology. Based on the underlying principle that radiation can be delivered in a targeted way by attaching a certain radionuclide to a molecule or antibody, which selectively accumulates in tumor necrosis and emits radiation to kill and/or restrain www.impactjournals.com/oncotarget adjacent residual cancer cells. Such a design belongs to internal molecular targeted radiotherapy [8]

Methods

Results

Conclusion