整合素αvβ3和基质金属蛋白酶-2/9双靶向PET探针构建及其在SKOV-3卵巢癌小鼠显像中的应用

卵巢癌是最常见的妇科肿瘤之一，因缺乏有效的早期诊断方法，病死率极高。整合素αvβ3表达和基质金属蛋白酶-2/9活性（MMP-2/9）在卵巢癌中特异性升高，且与其生长和转移密切相关。靶向整合素αvβ3和MMP-2/9的分子影像学显像有望成为卵巢癌早期诊断的有效手段。本课题拟以整合素αvβ3和活化的MMP-2/9为靶点，构建用于PET显像的双靶向探针18F-ACPP-RGD2。系统评价探针的稳定性、生物学毒性、体外靶向性、生物学分布及药代动力学特性。通过SKOV-3卵巢癌小鼠模型MicroPET显像评价18F-ACPP-RGD2对SKOV-3肿瘤的诊断效能，并通过体外免疫组织化学分析探讨探针靶向摄取的机制。本课题的实施将对整合素αvβ3和活化的MMP-2/9双靶向显像在卵巢癌的应用价值进行客观评价，也为其他整合素αvβ3和MMP-2/9双靶向显像研究提供实验依据。

Ovarian cancer is one of the most common gynecological malignancies with a high mortality due to lack of effective modality for early diagnosis. The expression of integrin αvβ3 and the activity of matrix metalloproteinase-2/9 (MMP-2/9) are specifically increased in ovarian cancer and are both closely associated with growth and metastasis of the tumor. Integrin αvβ3 and MMP-2/9 targeted molecular imaging promises to be an effective modality for early diagnosis of ovarian cancer. In this study, a dual-targeting probe 18F-ACPP-RGD2 will be prepared by using the integrin αvβ3 and activated MMP-2/9 as the targets. The stability, biological toxicity, targeting effect in vitro, biodistribution and pharmacokinetics will be systemically assessed. By undergoing MicroPET imaging on SKOV-3 xenograft-bearing mice, the tumor diagnostic efficiency of 18F-ACPP-RGD2 will be evaluated. And the targeting mechanism of the probe will be investigated by using the immunohistochemical analysis in vitro. This study will provide an objective evaluation on the application value of the integrin αvβ3 and MMP-2/9 dual-targeted imaging on ovarian cancer, and provide an experimental basis for other studies on integrin αvβ3 and MMP-2/9 dual-targeted imaging.