Evaluation of modified PEG-anilinoquinazoline derivatives as potential agents for EGFR imaging in cancer by small animal PET.
OBJECTIVE
The in vivo evaluation of three modified polyethylene glycol (PEG)-anilinoquinazoline derivatives labeled with (124)I, (18)F, and (11)C as potential positron emission tomography (PET) bioprobes for visualizing epidermal growth factor receptor (EGFR) in cancer using small animal PET.


METHODS
Xenograft mice with the human glioblastoma cell lines U138MG (lacking EGFR expression) and U87MG.wtEGFR (transfected with an overexpressing human wild-type EGFR gene) were used. Static and dynamic PET imaging was conducted for all three PEGylated compounds. Tumor necrosis, microvessel density, and EGFR levels were evaluated by histopathology and enzyme-linked immunosorbent assay.


RESULTS
Nineteen animal models were generated (two U138MG, three U87MG, 14 with both U138MG and U87MG bilateral masses). In static images, a slight increase in tracer uptake was observed in tumors, but in general, there was no retention of tracer uptake over time and no difference in uptake between U138MG and U87MG masses. In addition, no significant uptake was demonstrated in dynamic scans of the (18)F-PEG tracer. No necrosis was present except in four animals. MVD was 9.6 and 48 microvessels/×400 field in the U138GM and U87GM masses, respectively (p = 0.00008). Similarly, the microvessel grades were generally higher in the U87GM group (p = 0.002). Total EGFR amount was higher in U87MG than U138MG masses (p = 0.001), but the ratio of activated (pY1068) to total EGFR did not differ (p = 0.95).


CONCLUSIONS
PEGylated tracers labeled with (11)C, (124)I, and (18)F showed no significant difference in uptake between U138MG and U87MG glioblastoma xenograft mice. The tracer binding with EGFR could be influenced by activation of the tyrosine kinase portion of the receptor which was similar in U138MG and U87MG. Despite these results, these tracers should be investigated in animal models with mutant EGFR genes to determine whether aberrant receptor function plays a role in tumor uptake.
Pantaleo
Maria A
MA
Department of Hematology and Oncological Sciences L.A. Serganoli, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, Bologna, Italy. maria.pantaleo@unibo.it
Mishani
Eyal
E
Nanni
Cristina
C
Landuzzi
Lorena
L
Boschi
Stefano
S
Nicoletti
Giordano
G
Dissoki
Samar
S
Paterini
Paola
P
Piccaluga
Pier Poalo
PP
Lodi
Filippo
F
Lollini
Pier-Luigi
PL
Fanti
Stefano
S
Biasco
Guido
G
D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000493:pharmacokinetics; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D008954:Models, Biological; D057054:Molecular Imaging / Q000379:methods* / Q000662:veterinary; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods* / Q000662:veterinary; D011799:Quinazolines / Q000737:chemistry / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
D003287:Contrast Media; D011799:Quinazolines; D011092:Polyethylene Glycols; C541485:EGFR protein, mouse; D066246:ErbB Receptors