量子点标记探针技术的乳腺癌关键分子成像体系与个体化预警新方法

Quantum dots (QDs) are new semiconductor nanocrystals with core size ranging from 2 to 10 nm in diameter. The special quantum size and surface effect of QDs produces unique optical and electronic advantages over traditional organic fluorescent dyes, including superior fluorescence intensity, strong resistance to photobleaching and chemical degradation, size-tunable light emission, and simultaneous multiple fluorescent colors under single source excitation. QDs also have optimal surface chemistries to link with targets such as antibodies, peptides or small molecules, producing versatile bioprobes for biomedical application, especially in cancer research. The increasing understanding of the breast cancer (BC) biological behaviors has revolutionized BC treatment concept, and the personalized medicine for BC has become the dominant strategy in clinical practice, resulting improved survival and quality of life. Accurate classification is fundamental for BC personalized treatment. The essential classification based on anatomic information which can not display the biological characteristics of breast cancer, has been inadequate for BC treatment decision and prognosis prediction. The molecular-based BC classifications have improved the understanding of BC heterogeneity, which is fundamental in the era of individualized cancer care, a milestone in the BC treatment history. A typical example is the ever increasing understanding of the role of four key moleculars, human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), progesterone receptor (PR) and Ki67, which have been used as indicators of diagnosis, treatment strategies and prognosis prediction. However, the current methods for key molecular evaluation are single and semi-quantitative, which might not fully reveal the BC heterogeneity and could not more accurately identify BC subtypes for personalized care. Therefore, a quantitative and accurate method for personalized molecular prediction of breast cancer prognosis is highly desirable academically as well as clinically. This program is to develop a method for personalized molecular prediction of BC prognosis based on QDs labeled bioprobes previously. On the basis of further exert interdisciplinary strengths, we will establish a QDs bio-probe and quality control system, achieve the real-time, long-term, simultaneous molecular imaging in situ of these key molecules, and construct the a new method for individual prediction, promoting the personalized oncology.

新型荧光纳米量子点（Quantum dots，QDs）具有荧光发射波长可控、发射峰狭窄对称，激发谱宽而连续，消光系数大、荧光强度高、光稳定性好等优良光学特性。将量子点标记探针技术用于分子成像领域，有望推动肿瘤学研究。乳腺癌的个体化医疗是当今肿瘤诊疗的主流方向。针对乳腺癌关键分子人类表皮生长因子受体-2（HER2）、雌激素受体（ER）、孕激素受体（PR）和Ki67等的分子分类体系，已成为乳腺癌个体化医疗的里程碑。但传统的半定量、单指标检测技术及评估体系难以准确反映分子间的相互作用及个体间差异，限制了个体化医疗的进一步提高。本课题拟在前期构建的量子点标记探针关键分子成像体系的基础上，进一步发挥多学科交叉优势，建立量子点标记探针及性能控制体系，实现对上述关键分子的原位、实时、共定位、长时间量子点标记探针分子成像，构建乳腺癌关键分子个体化预警新方法，并评估预警效能，为乳腺癌的个体化医疗提供参考。

乳腺癌是女性最常见的恶性肿瘤，严重威胁女性生命健康。我国乳腺癌加速上升，发病人数快速增加，是我国的重大疾病负担。个体化医疗是乳腺癌未来诊疗方向。本项目从乳腺癌关键分子的准确评估与个体化预警基本问题出发，基于纳米量子点标记探针成像技术，在既往研究基础上，进一步优化筛选预警指标，并构建关键分子的原位、实时、共定位成像，在临床病例中评估其预警效能，通过对癌及微环境的多组分、多分子、原位共成像，深化了乳腺癌生物学行为的新认识，推动力乳腺癌的个体化医疗。本课题执行三年来，初步构建了乳腺癌病例信息资料库，并不断完善，分析了中部地区乳腺癌的病例特点，为我国乳腺癌防治提供了一定参考，同时基于该资料库进一步优化筛选了乳腺癌预警指标；其次，在既往研究基础上，进一步评估了乳腺癌关键分子EGFR和Ki67对新分类体系的补充预警价值，将细胞角蛋白（CK）与Ki67进行联合分析，结果表明，Ki67/CK比值具有更强的预警价值，为乳腺癌的精确预警提供了一个新指标。第三，基于量子点标记探针分子成像技术，对乳腺癌细胞与微环境关键分子相互作用进行了探索研究，实现了微环境关键分子CCL5与基金金属蛋白酶-9（MMP-9）的标记成像，癌细胞键分子HER2和微环境分子IV胶原的标记成像，揭示了乳腺癌的异质性，深化了对乳腺癌生物学行为的理解；同时在实现癌细胞关键分子EGFR和微环境关键分子IV共成像的同时，在三阴乳腺癌中分析了两关键分子的联合预警价值，表明EGFR/IV比具有更强的预测价值，是一个独立预后指标，为乳腺癌预后评估提供了一个新指标。本课题基本完成既定研究内容，已发表相关论文10篇，其中SCI论文8篇，已培养硕士生研究生1人，博士研究生3人；本课题在后续仍需深化合作，进一步完善病例信息库，优化筛选适合我国乳腺癌特点的预警指标；此外，量子点标记分子探针成像技术深入认识乳腺癌异质性方面具有独特优势，在后续研究中，将进一步筛选、优化预警分子，结合具体临床问题，通过多分子标记成像，进一步揭示乳腺癌的异质性，深化对乳腺癌生物学行为的理解，为制定个体化医疗策略提供理论和实践依据。