Theranostics 2013; 3(2):127-137. doi:10.7150/thno.5790

Research Paper

Sequential Systemic Administrations of Combretastatin A4 Phosphate and Radioiodinated Hypericin Exert Synergistic Targeted Theranostic Effects with Prolonged Survival on SCID Mice Carrying Bifocal Tumor Xenografts

Junjie Li1,2, Marlein Miranda Cona1,2, Feng Chen1,2, Yuanbo Feng1,2, Lin Zhou3, Guozhi Zhang1, Johan Nuyts3, Peter de Witte4, Jian Zhang5, Jie Yu1, Raymond Oyen6, Alfons Verbruggen4, Yicheng Ni1,2,5✉

1. Theranostic Laboratory, Department of Imaging & Pathology, Faculty of Medicine, Biomedical Sciences Group, KU Leuven, Herestraat 49, Leuven, Belgium.
2. Molecular Small Animal Imaging Centre/MoSAIC, Biomedical Sciences Group, KU Leuven, Herestraat 49, Leuven, Belgium.
3. Nuclear Medicine & Molecular Imaging, Department of Imaging & Pathology, Faculty of Medicine, Biomedical Sciences Group, KU Leuven, Herestraat 49, Leuven, Belgium.
4. Faculty of Pharmaceutical Sciences, Biomedical Sciences Group, KU Leuven, Herestraat 49, Leuven, Belgium.
5. Laboratory of Translational Medicine, Jiangsu Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu Province, China.
6. Radiology Section, Department of Imaging & Pathology, Faculty of Medicine, Biomedical Sciences Group, KU Leuven, Herestraat 49, Leuven, Belgium.

Abstract

Objectives: Based on the soil-to-seeds principle, we explored the small-molecular sequential dual-targeting theranostic strategy (SMSDTTS) for prolonged survival and imaging detectability in a xenograft tumor model.

Materials and Methods: Thirty severe combined immunodeficiency (SCID) mice bearing bilateral radiation-induced fibrosarcoma-1 (RIF-1) subcutaneously were divided into group A of SMSDTTS with sequential intravenous injections of combretastatin A4 phosphate (CA4P) and 131I-iodohypericin (131I-Hyp) at a 24 h interval; group B of single targeting control with CA4P and vehicle of 131I-Hyp; and group C of vehicle control (10 mice per group). Tumoricidal events were monitored by in vivo magnetic resonance imaging (MRI) and planar gamma scintiscan, and validated by ex vivo autoradiography and histopathology. Besides, 9 mice received sequential intravenous injections of CA4P and 131I-Hyp were subjected to biodistribution analysis at 24, 72 and 120 h.

Results: Gamma counting revealed fast clearance of 131I-Hyp from normal organs but intense accumulation in necrotic tumor over 120 h. After only one treatment, significantly prolonged survival (p<0.001) was found in group A compared to group B and C with median survival of 33, 22, and 21 days respectively. Tumor volume on day 15 was 2.0 ± 0.89, 5.66 ± 1.66, and 5.02 ± 1.0 cm3 with tumor doubling time 7.8 ± 2.8, 4.4 ± 0.67, and 4.5 ± 0.5 days respectively. SMSDTTS treated tumors were visualized as hot spots on gamma scintiscans, and necrosis over tumor ratio remained consistently high on MRI, autoradiography and histology.

Conclusion: The synergistic antitumor effects, multifocal targetability, simultaneous theranostic property, and good tolerance of the SMSDTTS were evident in this experiment, which warrants further development for preclinical and clinical applications.

Keywords: vascular disrupting agents (VDAs), necrosis targeting radiotherapy, radiation-induced fibrosarcoma-1 (RIF-1), survival, synergistic antitumor effects.

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How to cite this article:
Li J, Cona MM, Chen F, Feng Y, Zhou L, Zhang G, Nuyts J, de Witte P, Zhang J, Yu J, Oyen R, Verbruggen A, Ni Y. Sequential Systemic Administrations of Combretastatin A4 Phosphate and Radioiodinated Hypericin Exert Synergistic Targeted Theranostic Effects with Prolonged Survival on SCID Mice Carrying Bifocal Tumor Xenografts. Theranostics 2013; 3(2):127-137. doi:10.7150/thno.5790. Available from http://www.thno.org/v03p0127.htm