Are gadolinium contrast agents suitable for gadolinium neutron capture therapy?
OBJECTIVE
Gadolinium neutron capture therapy (GdNCT) is a potential treatment for malignant tumors based on two steps: (1) injection of a tumor-specific (157)Gd compound; (2) tumor irradiation with thermal neutrons. The GdNC reaction can induce cell death provided that Gd is proximate to DNA. Here, we studied the nuclear uptake of Gd by glioblastoma (GBM) tumor cells after treatment with two Gd compounds commonly used for magnetic resonance imaging, to evaluate their potential as GdNCT agents.


METHODS
Using synchrotron X-ray spectromicroscopy, we analyzed the Gd distribution at the subcellular level in: (1) human cultured GBM cells exposed to Gd-DTPA or Gd-DOTA for 0-72 hours; (2) intracerebrally implanted C6 glioma tumors in rats injected with one or two doses of Gd-DOTA, and (3) tumor samples from GBM patients injected with Gd-DTPA.


RESULTS
In cell cultures, Gd-DTPA and Gd-DOTA were found in 84% and 56% of the cell nuclei, respectively. In rat tumors, Gd penetrated the nuclei of 47% and 85% of the tumor cells, after single and double injection of Gd-DOTA, respectively. In contrast, in human GBM tumors 6.1% of the cell nuclei contained Gd-DTPA.


CONCLUSIONS
Efficacy of Gd-DTPA and Gd-DOTA as GdNCT agents is predicted to be low, due to the insufficient number of tumor cell nuclei incorporating Gd. Although multiple administration schedules in vivo might induce Gd penetration into more tumor cell nuclei, a search for new Gd compounds with higher nuclear affinity is warranted before planning GdNCT in animal models or clinical trials.
De Stasio
Gelsomina
G
University of Wisconsin-Madison, Department of Physics and Synchrotron Radiation Center, 3731 Schneider Drive, Stoughton, WI 53589, USA. pupa@src.wisc.edu
Rajesh
Deepika
D
Casalbore
Patrizia
P
Daniels
Matthew J
MJ
Erhardt
Robert J
RJ
Frazer
Bradley H
BH
Wiese
Lisa M
LM
Richter
Katherine L
KL
Sonderegger
Brandon R
BR
Gilbert
Benjamin
B
Schaub
Sebastien
S
Cannara
Rachel J
RJ
Crawford
John F
JF
Gilles
Mary K
MK
Tyliszczak
Tolek
T
Fowler
John F
JF
Larocca
Luigi M
LM
Howard
Steven P
SP
Mercanti
Delio
D
Mehta
Minesh P
MP
Pallini
Roberto
R
D000818:Animals; D001931:Brain Mapping; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D005682:Gadolinium / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005909:Glioblastoma / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D006573:Heterocyclic Compounds, 1-Ring / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D018810:Magnetic Resonance Angiography / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D013058:Mass Spectrometry / Q000379:methods; D009368:Neoplasm Transplantation / Q000379:methods; D017247:Neutron Capture Therapy / Q000379:methods*; D004369:Pentetic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use; D011859:Radiography / Q000379:methods; D011868:Radioisotopes / Q000627:therapeutic use*; D011877:Radionuclide Imaging; D051381:Rats; D013997:Time Factors; D014018:Tissue Distribution
D006573:Heterocyclic Compounds, 1-Ring; D011868:Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D004369:Pentetic Acid; D005682:Gadolinium