title: A dual-targeting anticancer approach: soil and seed principle.
abstract: OBJECTIVE
  To test the hypothesis that targeting the microenvironment (soil) may effectively kill cancer cells (seeds) through a small-molecular weight sequential dual-targeting theragnostic strategy, or dual-targeting approach.
  
  
  METHODS
  With approval from the institutional animal care and use committee, 24 rats were implanted with 48 liver rhabdomyosarcomas (R1). First, the vascular-disrupting agent combretastatin A4 phosphate (CA4P) was injected at a dose of 10 mg/kg to cause tumor necrosis, which became a secondary target. Then, the necrosis-avid agent hypericin was radiolabeled with iodine 131 to form (131)I-hypericin, which was injected at 300 MBq/kg 24 hours after injection of CA4P. Both molecules have small molecular weight, are naturally or synthetically derivable, are intravenously injectable, and are of unique targetablities. The tumor response in the dual-targeting group was compared with that in vehicle-control and single-targeting (CA4P or (131)I-hypericin) groups with in vivo magnetic resonance imaging and scintigrams and ex vivo gamma counting, autoradiography, and histologic analysis. Tumor volumes, tumor doubling time (TDT), and radiobiodistribution were analyzed with statistical software. P values below .05 were considered to indicate a significant difference.
  
  
  RESULTS
  Eight days after treatment, the tumor volume of rhabdomyosarcoma in the vehicle-control group was double that in both single-targeting groups (P < .001) and was five times that in the dual-targeting group (P < .0001), without treatment-related animal death. The TDT was significantly longer in the dual-targeting group (P < .0001). Necrosis appeared as hot spots on scintigrams, corresponding to 3.13% of the injected dose of (131)I-hypericin per gram of tissue (interquartile range, 2.92%-3.97%) and a target-to-liver ratio of 20. The dose was estimated to be 100 times the cumulative dose of 50 Gy needed for radiotherapeutic response. Thus, accumulated (131)I-hypericin from CA4P-induced necrosis killed residual cancer cells with ionizing radiation and inhibited tumor regrowth.
  
  
  CONCLUSIONS
  This dual-targeting approach may be a simple and workable solution for cancer treatment and deserves further exploitation.
authors.affiliation: Department of Radiology, University of Leuven, Campus Gasthuisberg, Herestraat 49, Leuven 3000, Belgium.
authors.forename: Junjie
authors.initials: J
authors.lastname: Li
authors.forename: Ziping
authors.initials: Z
authors.lastname: Sun
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Haibo
authors.initials: H
authors.lastname: Shao
authors.forename: Marlein Miranda
authors.initials: MM
authors.lastname: Cona
authors.forename: Huaijun
authors.initials: H
authors.lastname: Wang
authors.forename: Thierry
authors.initials: T
authors.lastname: Marysael
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Kristof
authors.initials: K
authors.lastname: Prinsen
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Dejian
authors.initials: D
authors.lastname: Huang
authors.forename: Johan
authors.initials: J
authors.lastname: Nuyts
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.forename: Bin
authors.initials: B
authors.lastname: Meng
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Fang
authors.forename: Peter
authors.initials: P
authors.lastname: de Witte
authors.forename: Yaming
authors.initials: Y
authors.lastname: Li
authors.forename: Alfons
authors.initials: A
authors.lastname: Verbruggen
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Wang
authors.forename: Luc
authors.initials: L
authors.lastname: Mortelmans
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.forename: Guy
authors.initials: G
authors.lastname: Marchal
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Ni
mesh_terms: D000818:Animals; D000873:Anthracenes; D007457:Iodine Radioisotopes; D010569:Perylene / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D051381:Rats; D012208:Rhabdomyosarcoma / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000873:Anthracenes; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D010569:Perylene; C004965:hypericin