Rapid detection of hypoxia-inducible factor-1-active tumours: pretargeted imaging with a protein degrading in a mechanism similar to hypoxia-inducible factor-1alpha.
OBJECTIVE
Hypoxia-inducible factor-1 (HIF-1) plays an important role in malignant tumour progression. For the imaging of HIF-1-active tumours, we previously developed a protein, POS, which is effectively delivered to and selectively stabilized in HIF-1-active cells, and a radioiodinated biotin derivative, (3-(123)I-iodobenzoyl)norbiotinamide ((123)I-IBB), which can bind to the streptavidin moiety of POS. In this study, we aimed to investigate the feasibility of the pretargeting method using POS and (123)I-IBB for rapid imaging of HIF-1-active tumours.


METHODS
Tumour-implanted mice were pretargeted with POS. After 24 h, (125)I-IBB was administered and subsequently, the biodistribution of radioactivity was investigated at several time points. In vivo planar imaging, comparison between (125)I-IBB accumulation and HIF-1 transcriptional activity, and autoradiography were performed at 6 h after the administration of (125)I-IBB. The same sections that were used in autoradiographic analysis were subjected to HIF-1alpha immunohistochemistry.


RESULTS
(125)I-IBB accumulation was observed in tumours of mice pretargeted with POS (1.6%ID/g at 6 h). This result is comparable to the data derived from (125)I-IBB-conjugated POS-treated mice (1.4%ID/g at 24 h). In vivo planar imaging provided clear tumour images. The tumoral accumulation of (125)I-IBB significantly correlated with HIF-1-dependent luciferase bioluminescence (R=0.84, p<0.01). The intratumoral distribution of (125)I-IBB was heterogeneous and was significantly correlated with HIF-1alpha-positive regions (R=0.58, p<0.0001).


CONCLUSIONS
POS pretargeting with (123)I-IBB is a useful technique in the rapid imaging and detection of HIF-1-active regions in tumours.
Ueda
Masashi
M
Radioisotopes Research Laboratory, Kyoto University Hospital, Faculty of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Kudo
Takashi
T
Kuge
Yuji
Y
Mukai
Takahiro
T
Tanaka
Shotaro
S
Konishi
Hiroaki
H
Miyano
Azusa
A
Ono
Masahiro
M
Kizaka-Kondoh
Shinae
S
Hiraoka
Masahiro
M
Saji
Hideo
H
D000818:Animals; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D019809:Streptavidin / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic
C106664:(3-iodobenzoyl)norbiotinamide; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D001710:Biotin; D019809:Streptavidin