Zhang Y, Hong H, Yang Y, Severin G, Engle J, Niu G, Chen X, Leigh B, Barnhart T, Cai W
University of Wisconsin - Madison, Madison, WI.
NIBIB, Bethesda, MD.
Med Phys. 2012 Jun;39(6Part27):3950. doi: 10.1118/1.4736120.
Metastatic breast cancer (MBC) is incurable. The clinical gold standard for assessing tumor microvessel density (MVD), an independent prognostic marker in MBC, is CD 105 staining. The goal of this study is to develop a positron emission tomography (PET)/near-infrared fluorescent (NIRF) probe for imaging of CD105 expression in MBC (i.e. non-invasive measurement of MVD), as well as other applications such as early detection of metastasis, intraoperative guidance, etc.
TRC105, a chimeric anti-CD105 mAb, was dual-labeled with a NIRF dye and Zr to yield Zr-Df-TRC105-800CW. Luciferase-transfected 4T1 murine breast cancer cells were injected intravenously into female BALB/c mice to establish a lung MBC model. Bio luminescence imaging (BLI) was carried out to non- invasively monitor the lung tumor burden. Comprehensive in vivo/ex vivo studies were performed to investigate Zr-Df-TRC105-800CW in this MBC model. Cetuximab was used as an isotype-matched control.
Radiolabeled TRC105 has high tumor uptake in many tumor types in addition to MBC (e.g. pancreatic/prostate cancer and brain tumor), revealing broad clinical potential for TRC105-based agents. FACS analysis of HUVECs showed no difference in CD 105 binding between TRC105 and Df- TRC105-800CW. PET imaging revealed that 4T1 lung tumor uptake of Zr-Df-TRC105-800CW was 8.7±1.4,10.9±0.5, and 9.7±1.1 %ID/g at 4, 24, and 48 h post-injection (n = 4), with excellent tumor contrast. Bio distribution studies, blocking, control studies with Zr-Df-cetuximab- 800CW, ex vivo BLI/PET/NIRF imaging, and histology all confirmed CD 105 specificity of the tracer. NIRF imaging-guided removal of 4T1 tumors with Df-TRC105-800CW in a subcutaneous model was also straightforward.
We report the first PET/NIRF imaging of CD105 expression in a MBC model. Broad clinical potential of TRC105- based agents was shown in many tumor types, which also enabled early detection of small metastases and provided intraoperative guidance for tumor removal.
转移性乳腺癌（MBC）无法治愈。评估肿瘤微血管密度（MVD）的临床金标准是CD 105染色，MVD是MBC中的一个独立预后标志物。本研究的目的是开发一种正电子发射断层扫描（PET）/近红外荧光（NIRF）探针，用于MBC中CD105表达的成像（即MVD的非侵入性测量），以及其他应用，如转移的早期检测、术中引导等。
将嵌合抗CD105单克隆抗体TRC105用NIRF染料和锆进行双标记，得到Zr-Df-TRC105-800CW。将荧光素酶转染的4T1小鼠乳腺癌细胞静脉注射到雌性BALB/c小鼠体内，建立肺MBC模型。进行生物发光成像（BLI）以非侵入性监测肺肿瘤负荷。在该MBC模型中对Zr-Df-TRC105-800CW进行了全面的体内/体外研究。西妥昔单抗用作同型对照。
除MBC外，放射性标记的TRC105在许多肿瘤类型中都有高肿瘤摄取（如胰腺癌/前列腺癌和脑肿瘤），揭示了基于TRC105的制剂具有广泛的临床潜力。对人脐静脉内皮细胞（HUVECs）的流式细胞术分析显示，TRC105和Df-TRC105-800CW之间的CD 105结合没有差异。PET成像显示，注射后4、24和48小时，Zr-Df-TRC105-800CW在4T1肺肿瘤中的摄取分别为8.7±1.4、10.9±0.5和9.7±1.1 %ID/g（n = 4），肿瘤对比度极佳。生物分布研究、阻断实验、用Zr-Df-西妥昔单抗-800CW进行的对照研究、体外BLI/PET/NIRF成像以及组织学均证实了该示踪剂的CD 105特异性。在皮下模型中，用Df-TRC105-标记的NIRF成像引导切除4T1肿瘤也很顺利。
我们报道了在MBC模型中首次对CD105表达进行PET/NIRF成像。基于TRC105的制剂在许多肿瘤类型中显示出广泛的临床潜力，这也能够早期检测小转移灶并为肿瘤切除提供术中引导。
