基于特异性荧光探针辅助精准判定乳腺癌保乳手术切缘的研究

Breast cancer is one of the main malignant tumors threating the health of women. Breast conserving surgery is an important operation method for breast cancer. Accurately identification and determining the edge of edge are the key point to ensure the success of the surgery. Latest near-infrared fluorescence imaging probes technology may assist in real-time detecting the tumor edges during the operation to resect the tumor accurately. Our previous working on near-infrared tumor targeted nanoparticles and carbon quantum dots targeted drug delivery which have been achieved the periodic results. On this basis, our project intend to form a new type fluorescence probes Fo-BCP, which can specific targeting the met upon the surface of breast cancer cells, with a kind of near-infrared fluorescent dyes MPFI-36 considered as high penetrability, high stability, high fluorescence intensity to assist clinical breast surgery more practically and effectively. Based on the project, a new technology platform for the fluorescent-guided breast conserving surgery will be further built. Therefore, the weaknesses and difficulties of breast conserving surgery, tumor margin detection and tumor complete resection, might be solved. By improving negative rate of the surgical cut edges, reducing the recurrence rate of breast cancer, the postoperative survival and survival quality of breast cancer survivors will be finally improved.

乳腺癌严重危害女性健康，保乳手术是治疗乳腺癌的重要手段，其中精准识别肿瘤、判定肿瘤边缘是确保保乳手术成功的关键。我们前期一直致力于对近红外肿瘤靶向纳米粒及碳量子点药物靶向递送等方面的研究，取得了阶段性的成果。据此，本项目将利用一种新型的高组织穿透性、高光稳定性、高荧光强度的近红外荧光染料MPFI-36，将其作为探针的荧光响应基元，通过脂肪链共价连接叶酸靶向基元，构建能与乳腺癌细胞靶向识别的荧光探针Fo-BCP，分别在细胞、动物及人离体标本层面对探针的特异性、灵敏度、生物安全性等技术指标进行验证，逐步改进探针的综合性能，并进一步构建荧光引导下乳腺癌保乳手术术中的新技术诊断平台，同时借助乳腺癌动物模型，探索此技术平台在乳腺癌保乳手术中原位、实时、快速、准确判定切缘的应用价值，为其临床应用奠定基础，从而达到临床实践过程中减少手术切缘阳性率，提高乳腺癌患者有效保乳率，改善患者生存质量的目标。

乳腺癌作为全球女性最常见的恶性肿瘤严重危害人类身心健康。现阶段临床缺乏有效的术中肿瘤成像手段，临床中亟待寻找更为快速、灵敏、简便的方法提高乳腺癌原发微小病变的筛检率，降低首诊患者临床分期，同时探寻保乳术中有效的成像手段精准切除肿瘤，规避乳腺癌淋巴及血行转移风险。基于小分子的荧光探针成像技术用于临床及基础科研中对肿瘤细胞及相关标志物的可视化和量化，相较于其他技术具有灵敏度高、无损快速分析及动态实时监测等优势。本课题针对乳腺癌高表达的分子标志物中兴胆固醇酯水解酶1（Neutral Cholesterol Ester Hydrolase 1, NCEH1），设计并研制出具备荧光信噪比高、专一性强且生物毒性低的NCEH1酶靶向“开关型”免洗近红外荧光探针分子CS-AX，在体外及体内水平对CS-AX探针的理化性能，生物学特性，与靶标结合特性、生化属性表征等进行初步研究，并进一步在细胞、动物水平及人离体肿瘤组织及乳腺癌动物模型上研究目标荧光探针的免洗开关性能、灵敏度、特异性以及安全性等技术指标，旨在建立新颖的肿瘤标志物检测技术及荧光引导手术平台，为临床乳腺癌的早期确诊精准切除探索新的方向和道路，在乳腺癌特异荧光探针制备基础上可建立起荧光可视化判定肿瘤切缘的保乳手术平台，为最终实现早期乳腺癌诊疗一体化提供理论与实验依据，也为其它肿瘤疾病的诊治提供借鉴意义。