Imaging the Modulation of Adenoviral Kinetics and Biodistribution for Cancer Gene Therapy.
See page 841 To explore systemic utilization of Epstein-Barr virus (EBV)-specific transcriptionally targeted adenoviruses, three vectors were constructed to examine kinetics, specificity, and biodistribution: adv.oriP.luc, expressing luciferase under EBV-specific control; adv.SV40luc, expressing luciferase constitutively; and adv.oriP.E1A.oriP.luc, a conditionally replicating adenovirus, expressing both luciferase and E1A. Bioluminescence imaging (BLI) was conducted on tumor-bearing severe combined immunodeficient (SCID) mice (C666-1, EBV-positive human nasopharyngeal cancer) treated intravenously (i.v.) with 3 × 108infectious units (ifu) of the adenoviral vectors. At 72 hours, adv.oriPluc demonstrated an 8.4-fold higher tumor signal than adv.SV40luc; adv.oriP.E1A.oriP.luc was 26.7-fold higher; however, a significant liver signal was also observed, necessitating further action to improve biodistribution. Several compounds were examined to this end, including norepinephrine, serotonin, clodronate liposomes, and STI571, to determine whether any of these measures could improve adenoviral biodistribution. Each of these interventions was assessed using BLI in mice i.v. injected with adv.oriP.luc. STI571 achieved the highest increase in tumor-to-liver ratio (TLR; 6.6-fold), which was associated with a 59% reduction in tumor interstitial fluid pressure (IFP) along with a decrease in platelet-derived growth factor-β receptor (PDGFβR) activation. This study reports the favorable modulation by STI571 of the biodistribution of adenoviral vectors, providing a potential approach to improving therapeutic outcome.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Division of Applied Molecular Oncology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Joseph D
JD
Mocanu
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Division of Applied Molecular Oncology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Kenneth W
KW
Yip
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Division of Applied Molecular Oncology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Nehad M
NM
Alajez
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Division of Applied Molecular Oncology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Wei
W
Shi
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Division of Applied Molecular Oncology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Jian-Hua
JH
Li
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Division of Applied Molecular Oncology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Sarah J
SJ
Lunt
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Division of Biophysics and Bioimaging, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Eduardo H
EH
Moriyama
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Division of Biophysics and Bioimaging, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Brian C
BC
Wilson
Department of Radiation Oncology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
Michael
M
Milosevic
Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Shatin, Hong Kong.
Kwok-Wai
KW
Lo
Department of Cell Biology, Faculty of Medicine, Free University, Amsterdam, Netherlands.
Nico van
NV
van Rooijen
Laboratoire de Biologie des Tumeurs Humaines, Institut Gustave, Roussy, Villejuif, France.
Pierre
P
Busson
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Division of Applied Molecular Oncology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
Carlo
C
Bastianutto
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Division of Applied Molecular Oncology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada. Electronic address: Fei-Fei.Liu@rmp.uhn.on.ca.
Fei-Fei
FF
Liu