MR凋亡分子成像评估曲妥珠单抗靶向治疗HER2阳性乳腺癌疗效的实验研究

HER-2 is expressed at high levels in 25% to 30% of breast cancers. HER-2-overexpressing breast tumors are characteristically more aggressive and are associated with shorter survival in patients. Trastuzumab is the optional targeted dug for HER2-positive breast cancer treatment, but many disadvantages including expensive cost and acquired resistance to treatment exist. Thus, it is important for optimizing the clinical therapy plan in time to assess early the targeted treatment effect of trastuzumab. Apoptosis can be earlier than morphology in predicting early response to trastuzumab at molecular level. According to the reported researches, based on Annexin-V and ultrasmall superparamagnetic iron oxide (USPIO), a novel MR molecular probe of apoptosis will be constructed in the following project. Its reliability of labeling the cells will be validated in vitro. MR images will be acquired after injection of the molecular probe in mice with HER2-positive breast cancer received targeted therapy of trastuzumab and then analyzed. Correlative analysis will be performed between MRI results and histological results. The aim of the project is to investigate the feasibility and reliability of MR molecular probe of apoptosis in predicting and monitoring early response to trastuzumab in HER2-positive breast cancer and provide some experimental supports for further clinical application of MR molecular imaging of apoptosis.

25%-30%乳腺癌过度表达HER-2，此类乳腺癌恶性度高，易复发转移，患者预后差。曲妥珠单抗是HER-2阳性乳腺癌治疗的首选靶向药物，但存在费用昂贵、易产生药物抵抗等不足之处。因此，早期评估其靶向治疗效果，对于及时调整临床治疗方案具有重要意义。肿瘤细胞凋亡情况能够在形态学改变之前在分子水平较早反映肿瘤对治疗的反应。基于前期研究基础和结果，本课题以Annexin-V和超小超顺磁性氧化铁纳米颗粒 (ultrasmall superparamagnetic iron oxide, SPIO) 为基础，构建MR凋亡分子成像探针，体外验证其标记凋亡细胞的可靠性，并将其注入接受曲妥珠单抗靶向治疗的HER-2阳性乳腺癌荷瘤裸鼠体内，行MR分子成像，将MRI结果与组织学结果对照分析，探讨MR凋亡分子成像早期预测、评估曲妥珠单抗靶向治疗乳腺癌疗效的可行性和可靠性，为进一步推广应用提供实验基础和依据。

曲妥珠单抗是HER-2阳性乳腺癌治疗的首选靶向药物，但存在费用昂贵、易产生药物抵抗等不足之处。早期监测评估其靶向治疗效果，对于及时调整临床治疗方案具有重要意义。肿瘤细胞凋亡能够在肿瘤形态学改变之前在分子水平较早反映肿瘤对治疗的反应。本研究着重探讨MR凋亡分子成像早期预测、评估曲妥珠单抗靶向治疗HER-2阳性乳腺癌疗效的可行性。本研究以Annexin-V和超小超顺磁性氧化铁纳米颗粒为基础，成功构建MR凋亡分子成像探针；细胞普鲁士蓝染色证实MR凋亡分子成像探针可以有效磁性标记经曲妥珠单抗诱导凋亡的HER-2阳性乳腺癌细胞；细胞体外MR T2WI成像显示MR凋亡分子成像探针磁性标记的凋亡乳腺癌细胞信号显著低于磁性标记的正常细胞及非特异探针磁性标记的凋亡细胞的信号；曲妥珠单抗靶向治疗的HER-2阳性乳腺癌荷瘤裸分别在注射MR凋亡分子成像探针后行MR T2WI成像，肿瘤信号相比注射探针之前显著降低；而未治疗组在注射探针前后、治疗组在注射非特异探针前后肿瘤信号均未见明显变化；免疫组织化学染色及普鲁士蓝染色显示曲妥珠单抗靶向治疗肿瘤组织内Caspase-3表达及铁染色阳性。本研究结果表明MR凋亡分子成像可以有效地早期预测、评估曲妥珠单抗靶向治疗HER-2阳性乳腺癌疗效，为肿瘤患者的个体化分子靶向治疗提供分子影像学信息。