基于细胞衰老表型的超声靶向探针评估Her-2阳性乳腺癌的靶向治疗后耐药

About 15% -25% of breast cancer patients present Her-2 over-expression, while patients with Her-2 over expression often suggests poor prognosis. Herceptin plays an important role in targeted therapy for Her-2-positive breast cancer patients. However, during the clinical treatment, effective remission rate of single drug treatment is about 30%. Apoptosis and cell senescence are two critical phenomena after tumor cells treatment. After Herceptin treatment of Her-2-positive breast cancer cells, part of the tumor cells bypass the apoptosis phase, and directly into the cell senescence, due to lack of apoptosis process. The escape from cell senescence into cells proliferation has been considered as an important mechanism of drug resistance in breast cancer targeted therapy. Based on the previous preparation of ultrasound targeted molecular and experience on its application in the in vivo experiment, we will construct an ultrasound molecular probe targeted tumor cellular senescence. Its reliability of labeling the cells will be validated in vitro. Ultrasound imaging will be performed after injection of the molecular probe in mice with Her-2 positive breast cancer with senescence phenotype received drug therapy of Herceptin to monitor the change of tumor cellular senescence during different time points. The aim of the project is to investigate the feasibility and reliability of ultrasound molecular probe targeted tumor cellular senescence in predicting and monitoring drug resistance to Herceptin in Her-2 positive breast cancer.

约15%-25%的乳腺癌患者过度表达Her-2，同时Her-2过表达往往提示预后较差。以赫赛汀为代表的靶向药物治疗是目前Her-2阳性乳腺癌患者的重要靶向治疗手段。但在临床治疗过程中，单药有效缓解率在30%左右。细胞凋亡与细胞衰老是肿瘤细胞接受治疗后出现的两个重要现象。目前发现Her-2阳性乳腺癌细胞赫赛汀靶向处理后，部分未被清除的肿瘤细胞旁路绕过凋亡过程直接进入细胞衰老阶段，而衰老后肿瘤细胞重新增殖的现象，被认为是乳腺癌靶向治疗后耐药复发的主要原因之一。本研究拟在前期超声靶向分子探针成功制备的基础上，构建基于细胞衰老表型的超声分子探针，体外验证其标记细胞衰老现象的可靠性，随后将其注入接受靶向药物治疗，具有细胞衰老表型的Her-2阳性乳腺癌荷瘤裸鼠体内，在不同时间点行超声分子成像，监测肿瘤内部细胞衰老表型的变化，验证超声靶向成像评估乳腺癌赫赛汀治疗后耐药的有效性。

HER-2阳性乳腺癌靶向治疗容易导致细胞衰老和获得性耐药性的出现。我们旨在探索HER-2阳性乳腺癌细胞衰老与靶向治疗耐药的相关性，构建靶向纳米泡验证超声靶向成像评估乳腺癌靶向治疗后耐药的有效性。通过体内和体外实验，我们发现HER-2阳性乳腺癌在lapatinib/trastuzumab治疗后细胞发生衰老，停药后衰老细胞再次增殖。衰老是HER-2阳性乳腺癌拉帕替尼耐药的原因之一。NT5E可能是细胞衰老的有效标志物。超声靶向纳米泡NT5E- FITC-NBs在B模和超声造影检测中均具有较高的衰老细胞结合能力和良好的成像效果。然后构建HER-2阳性乳腺癌衰老动物模型。动物经拉帕替尼/曲妥珠单抗治疗后，肿瘤缩小，发光信号增强，超声回声强度增加。帕替尼/曲妥珠单抗停药一段时间后，肿瘤体积增大，发光信号减弱，超声回波强度降低。证明超声成像NT5E-FITC-NBs可有效评价lapatinib/trastuzumab诱导的HER-2阳性乳腺癌细胞衰老。临床数据表明，基于NT5E的超声靶向纳米泡作为衰老靶点具有临床转译的潜力。因此，基于细胞衰老的超声靶向成像可动态监测和有效评估HER-2阳性乳腺癌的靶向治疗耐药，具有临床转化的潜力。

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