Payen Thomas, Dizeux Alexandre, Baldini Capucine, Le Guillou-Buffello Delphine, Lamuraglia Michele, Comperat Eva, Lucidarme Olivier, Bridal S Lori
Laboratoire d'Imagerie Biomédicale, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Paris, France.
Laboratoire d'Imagerie Biomédicale, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Paris, France; Medical Oncology Department, Hopital Louis-Mourier, AP-HP, Colombes, France.
Ultrasound Med Biol. 2015 Aug;41(8):2202-11. doi: 10.1016/j.ultrasmedbio.2015.04.010. Epub 2015 May 15.
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.
本研究的目的是评估BR55（一种特异性靶向血管内皮生长因子受体2（VEGFR2）的超声造影剂）区分舒尼替尼的特异性抗VEGFR2治疗效果与另一种不直接抑制VEGFR2的治疗（伊马替尼）的其他抗血管生成效果的能力。将舒尼替尼、伊马替尼和安慰剂每日给药45只携带异位CT26小鼠结直肠癌的BalbC小鼠，持续11天（264小时）。在治疗过程中，分别进行B型超声、超声造影和VEGFR2靶向超声造影，以评估肿瘤形态、血管生成和VEGFR2表达。使用肿瘤体积、造影增强面积和差异靶向增强来表征这三个方面的血管生成效应。坏死、微血管和VEGFR2的表达也通过组织学和免疫染色来确定。B型成像显示，在第11天，舒尼替尼治疗的小鼠肿瘤生长显著降低（p<0.05），而伊马替尼对肿瘤生长没有影响。功能评估显示，在第8天（192小时），两种抗血管生成治疗下的造影增强面积均显著降低（p<0.02），且降低幅度相似：伊马替尼为-23%，舒尼替尼为-21%。安慰剂组未观察到显著降低。靶向超声造影成像显示，与安慰剂治疗的小鼠相比，舒尼替尼治疗的小鼠在24小时后差异靶向增强较低，即VEGFR2表达水平较低（p<0.05），与安慰剂和伊马替尼治疗的小鼠相比，在48小时后差异靶向增强也较低（p<0.05）。最终成像后对肿瘤的组织学评估表明，舒尼替尼组的坏死面积（21%）显著高于安慰剂组（8%，p<0.001）和伊马替尼组（11%，p<0.05）。VEGFR2靶向超声能够灵敏地区分抗VEGFR2效应与两种抗血管生成药物产生的具有功能性血流的肿瘤面积减小。因此，BR55分子成像既能在治疗开始后24小时就检测到CT26肿瘤对舒尼替尼的早期治疗反应，又能在靶向VEGFR2表达的抗血管生成治疗期间和不直接作用于该受体的抗血管生成治疗期间的肿瘤反应之间提供早期区分（48小时）。
