title: 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.
abstract: OBJECTIVE
  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.
  
  
  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 (131)I-iodohypericin ((131)I-Hyp) at a 24 h interval; group B of single targeting control with CA4P and vehicle of (131)I-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 (131)I-Hyp were subjected to biodistribution analysis at 24, 72 and 120 h.
  
  
  RESULTS
  Gamma counting revealed fast clearance of (131)I-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 cm(3) 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.
  
  
  CONCLUSIONS
  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.
authors: Theranostic Laboratory, Department of Imaging & Pathology, Faculty of Medicine, Biomedical Sciences Group, KU Leuven, Herestraat 49, Leuven, Belgium.
authors: Junjie
authors: J
authors: Li
authors: Marlein Miranda
authors: MM
authors: Cona
authors: Feng
authors: F
authors: Chen
authors: Yuanbo
authors: Y
authors: Feng
authors: Lin
authors: L
authors: Zhou
authors: Guozhi
authors: G
authors: Zhang
authors: Johan
authors: J
authors: Nuyts
authors: Peter
authors: P
authors: de Witte
authors: Jian
authors: J
authors: Zhang
authors: Jie
authors: J
authors: Yu
authors: Raymond
authors: R
authors: Oyen
authors: Alfons
authors: A
authors: Verbruggen
authors: Yicheng
authors: Y
authors: Ni
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000873:Anthracenes; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005354:Fibrosarcoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D006651:Histocytochemistry; D006801:Humans; D007457:Iodine Radioisotopes / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010569:Perylene / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011859:Radiography; D011877:Radionuclide Imaging; D013267:Stilbenes / Q000008:administration & dosage*; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; D007457:Iodine Radioisotopes; D013267:Stilbenes; D010569:Perylene; C004965:hypericin; C058728:fosbretabulin
keywords: necrosis targeting radiotherapy; radiation-induced fibrosarcoma-1 (RIF-1); survival; synergistic antitumor effects.; vascular disrupting agents (VDAs)