新型大黄酸类坏死靶向MRI探针用于肿瘤热消融早期疗效评价及其基于后标记法的机制研究

Early evaluation of tumor response to thermal ablation therapy can help to identify untreated tumor cells and then perform repeated treatment as soon as possible. Therefore, there is an unmet need for non-toxic, small-molecule based probes for treatment response evaluation, despite the active research in this area. Quantifcation of tumor necrosis in cancer patients is of diagnostic value to predict early effcacy of thermal ablation therapy. Our groups have proved that anthraquinones can achieve potent necrosis targeting ability and specifcally accumulate in necrotic tissue. After structural optimization, we found that Rhein exhibited necrosis targetability and excellentpharmacokinetic properties. Rhein-based SPECT-CT probes have been successfully used for imaging necrotic myocardium caused by myocardial infarction (MI). Considering the advantages of Magnetic Resonance Imaging (MRI) in imaging ablative margin, we will construct rhein-based necrosis-avid MRI contrast agents with the aim to evaluate their efficacy in early assessment of thermal ablation response. At the same time, the mechanism of this probe is not clear, and preliminary experiments show that the probe may achieve necrosis targetability through binding to the exposed DNA of necrosis cells. In this project, we would to examine whether rhein-based necrosis-avid MRI contrast agents can be used to predict early effcacy of thermal ablation treatments and study its mechanism using post-labeling method. This project will provide new idea for early assessment of tumor thermal ablation effectiveness.

肿瘤热消融治疗效果的早期评价有助于发现手术是否完全并及时调整治疗方案，临床上迫切需要高效的分子探针进行治疗效果的早期评估，如针对死亡细胞的成像探针。课题组前期研究并证实了蒽醌类化合物具有坏死靶向性，经过结构筛选，发现大黄酸(rhein)具有更优的药代动力学性质及较强的坏死靶向性。经核素标记后，已成功应用于大鼠心梗模型上坏死心肌的成像。但是核医学成像空间分辨率低，且有电离辐射，而磁共振成像 MRI 具有更高的空间分辨率，更符合清晰成像消融边界的需求。因此我们将构建基于rhein的 MRI 探针，用于肿瘤热消融早期治疗效果评价。同时该类探针的作用机制尚不明确，初步研究可能是通过与暴露的DNA结合实现坏死靶向性。因此，本项目拟考察基于rhein的磁共振探针能否用于肿瘤热消融早期治疗效果的评价，并且应用细胞水平的后标记荧光法研究该类坏死探针的作用机制。本项目将为肿瘤热消融治疗效果评价提供新的策略。

热消融术后早期疗效评价可以及时发现未经消融的残存肿瘤，并予以二次消融或其他补充治疗，避免治疗过度或不及。临床上迫切需要高效的分子探针进行治疗效果的早期评估。本项目拟考察基于rhein的磁共振探针能否用于肿瘤热消融早期治疗效果的评价，并且应用细胞水平的后标记荧光法研究该类坏死探针的作用机制。.首先造影剂的优选，GdL2成像微波消融所致坏死效果更好，且安全性高，因而选取GdL2开展本文后续工作。接下来研究GdL2的体内代谢性质及成像微波消融所致坏死的时间窗，结果表明GdL2可以实现消融术后早期疗效评价，并且具有良好的代谢性质。最后在大鼠肝脏肿瘤微波消融模型上考察GdL2成像消融所致坏死的效果，GdL2可以特异性地准确地成像微波消融所致坏死区域，具有用于微波消融术后疗效评价的潜力。综上所述，GdL2具有较低毒性、良好的代谢性质及成像微波消融所致坏死的能力，在微波消融术后2-24 h可显著增强消融所致坏死区域，成像时间窗为给药后2.5-3.5 h，具有开发用于微波消融术后早期疗效评价的潜力。.同时，我们设计了后标记法，通过激光共聚焦定位到探针主要分布到坏死细胞的细胞核，结合电泳实验、紫外、荧光及分子对接等实验，我们推测，大黄酸类坏死探针主要是通过与坏死细胞暴露的DNA结合从而实验坏死靶向性。

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