乳腺癌裸鼠模型αvβ3表达的PET/MRI活体分子影像学研究

Breast cancer has become the most frequent malignant tumor of the female.The annual death of breast cancer patients is about 500,000 and the mobidity will increase 1.2 million every year globally. The integrin plays a indispensible role in the angiogenesis of breast cancer. The αvβ3 is the most relevant one. The αvβ3 takes effects via regulating the endothelial functions including adhesion, migration, proliferation, and apoptosis.The ligand of αvβ3, RGD, is a short peptide. Given the affinity RGD to αvβ3, RGD is designed to combine the USPIO of self-owned intellectual property rights forming RGD-USPIO targeting αvβ3. And the probe will combine with F18 to make a new probe with double targeting effects, 18F-RGD-USPIO. The new probe will be implemented to image angiogenesis of breast cancer implanted in nude mouse model. Furthermore, it will be used to monitor and evaluate the therepeutic effects of antiangiogenesis agents on breast cancer model. Up to now, there's no literature concerning the 18F-RGD-USPIO as a probe with double targeting effects in PET/MR molecular imaging of angiogenesis of breast cancer.It is of great significance that the study on the development of the probe and its related imaging experiment is associated with ocurrence and early detection of the angiogenesis, and new drug development as well as evaluation of the therapeutic effects of antiangiogenesis.

乳腺癌已成为女性最常见的恶性肿瘤，全球每年50万人死于乳腺癌，并新增120万患者。整合素在乳腺癌血管生成中具有不可或缺的作用，以αvβ3整合素与肿瘤血管生成关系最为密切。αVβ3是通过调节内皮细胞的黏附、迁移、增殖、凋亡等功能，在肿瘤血管生成的过程中发挥它的作用的。αvβ3的配体RGD是一种短肽，根据RGD与αvβ3可特异性结合的特点，本研究拟采用RGD与具有自主产权的纳米粒USPIO偶联，构建成以αvβ3为靶标的分子探针RGD-USPIO，然后再连接F18，形成具有双重靶向性的特异性探针：F18-RGD-USPIO，对乳腺癌裸鼠模型进行PET和MR分子成像研究，并观察抗血管生成的疗效。尚未见以F18-RGD-USPIO为双重靶向探针进行乳腺癌血管生成PET/MR分子成像研究的报道。本研究中分子探针及其活体成像研究对评估血管生成的发生、早期诊断、抗血管生成新药开发及评估疗效等具有重要价值。

整合素αVβ3通过调节内皮细胞黏附、迁徙、增殖等过程在乳腺癌血管生成中发挥着不可或缺的作用。本项目研制出了以整合素αvβ3为靶点的MRI/PET双模态分子探针18F-RGD-PAA-USPIO，完成了对其弛豫率、粒径大小等理化性能的评估，体外验证了其靶向结合的能力，并应用于乳腺癌裸鼠皮下移植瘤的MRI及PET分子成像研究，进一步探讨了靶向性纳米分子探针18F-RGD-PAA-USPIO在乳腺癌裸鼠皮下移植瘤模型贝伐单抗抗血管生成治疗早期疗效评估方面的价值，取得良好效果。综上所述，本研究的结果显示，基于18F-RGD-PAA-USPIO的MR分子成像为乳腺癌等实体肿瘤的早期诊断、针对肿瘤血管生成的检测、抗血管治疗疗效评估等提供非侵入性的检查手段，具备潜在的临床应用前景。