基于整合素αvβ3受体的靶向磁共振/近红外双模式分子探针成像对人鼻咽癌裸鼠移植瘤转移的研究

Distant metastasis of nasopharyngeal carcinoma is one of the main reasons for treatment failure after rational radiation therapy and reasonable comprehensive treatment. Distant metastasis process has to rely on angiogenesis, and integrin αvβ3 plays an important role in the angiogenic procedure, and high expression of integrin αvβ3 may indicate the risk of distant metastasis of nasopharyngeal carcinoma. Currently, the detecting expression of integrin αvβ3 is always using an enzyme immunoassay, flow cytometry, etc., but these techniques have some shortcomings, such as existing invasion, poor reproducibility, no real-time dynamic monitoring. So, establishing an effective, non-invasive, real-time dynamic technical method to detect the expression of integrin αvβ3 state is dispensable. The new method is crucial to assess the efficacy of integrin αvβ3 -based drug research and development, and is urgent to address integrin αvβ3-based risk of nasopharyngeal carcinoma metastasis and prognosis prediction. For the reason, the project in well-differentiated human nasopharyngeal carcinoma in nude mice model by use of MRI / fluorescence dual-mode molecular imaging probes (cRGD-USPIO-Cy5.5) will investigate the dynamic integration of quantified monitoring of nasopharyngeal carcinoma αvβ3 integrin expression and efficacy αvβ3 targeting molecular targeted treatment , etc.. The purpose is predicting and assessing integrin αvβ3-based risk metastasis of nasopharyngeal carcinoma, and provides a noninvasive and effective tools for integrin αvβ3-based molecular targeted treatment.Thereby, the project of nasopharyngeal carcinoma integrin αvβ3 -based research is more important scientific significance and potential clinical applications.

远处转移是鼻咽癌治疗失败的主要原因之一。鼻咽癌远处转移须依赖新生血管生成，整合素αvβ3在血管生成过程中起着重要作用，其高表达是肿瘤发生转移的重要指标。目前对整合素αvβ3表达的检测方法仍存在有创、重复性差、难以实现实时动态监测等缺点。本项目拟采用cRGD偶联 Cy5.5和USPIO组合成适用于磁共振/荧光双模式分子成像的双功能分子探针 (cRGD-USPIO-Cy5.5)，并借助于鼻咽癌裸鼠模型，针对cRGD-USPIO-Cy5.5介导的磁共振/荧光双模式分子成像技术是否适用于动态和量化监测鼻咽癌动物模型的整合素αvβ3表达情况以实现对鼻咽癌转移的预测、是否适用于动态评估以整合素αvβ3为靶点的分子靶向治疗效果等研究目标，开展系统性的研究工作。本研究有望为预测鼻咽癌转移风险和评估鼻咽癌分子靶向治疗效果提供无创而有效的新技术手段，故本研究具有较重要的科学意义和潜在的临床应用价值。

鼻咽癌的浸润及远处转移是导致其治疗失败的主要原因，恶性肿瘤的血行转移过程必须依赖细胞外基质的破坏及肿瘤新生血管的形成。整合素αvβ3是目前备受关注且正处于广泛研究阶段的肿瘤新生血管分子标志物，其与肿瘤新生血管形成过程中血管内皮细胞的黏附、增殖、分化密切相关。目前检测整合素αvβ3表达水平的方法在有创性、可重复性差以及成像时效性差等方面的问题仍亟待解决。有鉴于此，针对上述客观存在的问题，本项目中合成双模态成分子探针以实时、动态靶向整合素αvβ3的表达状态,从而间接达到预测并监测肿瘤转移的目的。首先，利用薄膜分散法合成载三氯化钆脂质体，在其表面偶联RGD环肽和荧光Cy5.5分子，得到双模态分子探针cRGD-Gd-Cy5.5。通过透射电镜、动态光散射、粒径分析仪和多功能酶标仪测定cRGD-Gd-Cy5.5的表征，进而利用分子探针在体外细胞和鼻咽癌裸鼠移植瘤模型上进行磁共振/荧光分子成像。结果显示通过薄膜分散法制备磁共振分子探针cRGD-Gd-Cy5.5具有良好表征，体内外MR/NIR分子影像成像实验上证实分子探针cRGD-Gd-Cy5.5对整合素αvβ3有较好的靶向性，提示以分子探针cRGD-Gd-Cy5.5为造影剂的MR/NIRF分子成像可实现鼻咽癌的整合素αvβ3在解剖学水平和分子代谢水平的无创、高效、动态监测。本项目资助发表论文15篇（SCI4篇），培养硕士生2名。综上所述，本研究结果为探讨有效、无创、可实现实时动态监测整合素αvβ3表达情况提供行之有效的技术手段，同时对预测鼻咽癌转移风险提供了重要的启示性线索，为基于鼻咽癌整合素αvβ3的分子靶点治疗药物研究和开发奠定了坚实的工作基础。

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