title: VEGFR2-Targeted Contrast-Enhanced Ultrasound to Distinguish between Two Anti-Angiogenic Treatments.
abstract: The aim of this study was to evaluate the capacity of BR55, an ultrasound contrast agent specifically targeting vascular endothelial growth factor receptor 2 (VEGFR2), to distinguish the specific anti-VEGFR2 therapy effect of sunitinib from other anti-angiogenic effects of a therapy (imatinib) that does not directly inhibit VEGFR2. Sunitinib, imatinib and placebo were administered daily for 11 d (264 h) to 45 BalbC mice bearing ectopic CT26 murine colorectal carcinomas. During the course of therapy, B-mode ultrasound, contrast-enhanced ultrasound and VEGFR2-targeted contrast-enhanced ultrasound were performed to assess tumor morphology, vascularization and VEGFR2 expression, respectively. The angiogenic effects on these three aspects were characterized using tumor volume, contrast-enhanced area and differential targeted enhancement. Necrosis, microvasculature and expression of VEGFR2 were also determined by histology and immunostaining. B-Mode imaging revealed that tumor growth was significantly decreased in sunitinib-treated mice at day 11 (p < 0.05), whereas imatinib did not affect growth. Functional evaluation revealed that the contrast-enhanced area decreased significantly (p < 0.02) and by similar amounts under both anti-angiogenic treatments by day 8 (192 h): -23% for imatinib and -21% for sunitinib. No significant decrease was observed in the placebo group. Targeted contrast-enhanced imaging revealed lower differential targeted enhancement, that is, lower levels of VEGFR2 expression, in sunitinib-treated mice relative to placebo-treated mice from 24 h (p < 0.05) and relative to both placebo- and imatinib-treated mice from 48 h (p < 0.05). Histologic assessment of tumors after the final imaging indicated that necrotic area was significantly higher for the sunitinib group (21%) than for the placebo (8%, p < 0.001) and imatinib (11%, p < 0.05) groups. VEGFR2-targeted ultrasound was able to sensitively differentiate the anti-VEGFR2 effect from the reduced area of tumor with functional flow produced by both anti-angiogenic agents. BR55 molecular imaging was, thus, able both to detect early therapeutic response to sunitinib in CT26 tumors as soon as 24 h after the beginning of the treatment and to provide early discrimination (48 h) between tumor response during anti-angiogenic therapy targeting VEGFR2 expression and response during anti-angiogenic therapy not directly acting on this receptor.
authors.affiliation: Laboratoire d'Imagerie Biomédicale, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Payen
authors.affiliation: Laboratoire d'Imagerie Biomédicale, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dizeux
authors.affiliation: Laboratoire d'Imagerie Biomédicale, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Paris, France.
authors.forename: Capucine
authors.initials: C
authors.lastname: Baldini
authors.affiliation: Laboratoire d'Imagerie Biomédicale, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Le Guillou-Buffello
authors.affiliation: Laboratoire d'Imagerie Biomédicale, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Paris, France; Medical Oncology Department, Hopital Louis-Mourier, AP-HP, Colombes, France.
authors.forename: Michele
authors.initials: M
authors.lastname: Lamuraglia
authors.affiliation: Anatomic Pathology Department, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.
authors.forename: Eva
authors.initials: E
authors.lastname: Comperat
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, AP-HP, Laboratoire d'Imagerie Biomédicale, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lucidarme
authors.affiliation: Laboratoire d'Imagerie Biomédicale, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Paris, France. Electronic address: lori.bridal@upmc.fr.
authors.forename: S Lori
authors.initials: SL
authors.lastname: Bridal
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003287:Contrast Media / Q000493:pharmacokinetics*; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D000068877:Imatinib Mesylate / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D057054:Molecular Imaging / Q000379:methods; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D000077210:Sunitinib; D016896:Treatment Outcome; D014463:Ultrasonography / Q000379:methods*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D007211:Indoles; D011758:Pyrroles; D000068877:Imatinib Mesylate; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib
keywords: Anti-angiogenic treatment; Targeted microbubbles; Ultrasound; Vascular endothelial growth factor receptor 2