肿瘤相关巨噬细胞活体成像及胃癌预后研究

Tumor-associated macrophages (TAMs) have been realized as a key factor in malignant tumor proliferation, invasion, recurrence, and metastasis related events. A majority of clinical studies have demonstrated that richer TAM infiltration often gives rise to faster tumor progress and lower patient survival rate, however, it still remains challenging to visualize and monitor the TAMs in a secure and non-invasive mode. To serve this clinical demand, in this proposal, non-cadmium I-III-VI quantum (QDs) with satisfied biosafety will be chosen for constructing fluorescence/magnetic nanoprobes, in order to achieve dual-modality imaging and meantime quantification of TAMs. Such nanoprobes will benefit from complementary and mutually confirmed advantages from different imaging modality: real-time optical imaging with high-sensitivity and contrast-enhanced magnetic resonance imaging with high tissue penetration depth. Rational design and buildup of core/shell and doping structures will be investigated for obtaining magnetic QDs with tunable near-infrared fluorescence and enhanced relaxometric performance as well. Design of particle biomimic molecules such as “self peptide” and “zwitterion” ligands will be carried out in order to investigate the surface modification strategies for resulting particle and obtain the nanoprobes which can not only actively target TAMs but also possess the effective immune escape ability. These nanoprobes will be used for in vivo imaging of TAMs, and in combination with high-throughput detection method, detailed extracting and quantitatively analyzing the imaging information of infiltration density and phenotypic polarization of TAMs during gastric cancer tumor progression and intervention therapy, and meanwhile the assess prognosis will be investigated. This proposal provides a promising strategy for tumor progression/prognosis monitoring and individualized treatments in malignant tumors.

肿瘤相关巨噬细胞（TAMs）是恶性肿瘤增殖、侵袭、转移及复发等事件的关键因素，大量临床研究表明TAMs丰富的肿瘤发展更快，患者生存率更低，而以安全无创模式对TAMs进行可视化检测仍然面临挑战。针对这一临床需求，本项目拟以生物安全性优异的无镉I-III-VI族量子点为信号载体构建荧光/磁性纳米探针，通过不同影像信息的优势互补及相互印证—实时动态且高灵敏的近红外光学成像及高组织穿透深度的磁共振造影对比增强成像，以实现TAMs的双模态活体成像及定量检测。拟结合核壳及掺杂结构制备近红外发光可调、磁共振造影性能高效的磁性量子点，设计合成自身肽和两性离子分子以探究可TAMs主动靶向且可有效免疫逃逸的探针表面仿生修饰方法。以胃癌模型研究探针对TAMs的双模态活体成像，结合高通量检测研究肿瘤进展及干预中TAMs浸润密度和表型极化的影像学信息定量解析并评估预后，为肿瘤进展、预后监测及个体化治疗提供新的策略。

高灵敏、高分辨的活体光学/磁共振多模态纳米分子影像探针是本项目的核心内容。肿瘤免疫微环境浸润的肿瘤相关巨噬细胞是恶性肿瘤增殖、侵袭、转移及复发等事件的关键因素，大量临床研究表明浸润丰富的肿瘤发展更快，患者生存率更低，而以安全无创模式的在体可视化检测仍然面临挑战。本项目针对这些检测需求，深入研究了灵敏度高、特异性强、稳定性高的活体肿瘤相关纳米成像探针的构建和在体应用方法，取得了如下成果：1）基于量子点（半导体纳米晶）发展了多种本征光学及磁性性能优异的多模态纳米分子影像探针，揭示了探针近红外发光性能的生长动力学和晶体结构调控机制，为多功能半导体纳米晶的医学研究和应用奠定了基础；2）结合表面生物相容性修饰，利用生物安全性优异的无镉近红外量子点为信号载体构建主动靶向型的近红外荧光/磁性双模态纳米探针，发展了活体肿瘤的高灵敏可视化检测方法，精准描绘了肿瘤边界；3）通过优选鉴定不同巨噬细胞的特征分子标志物，发展了在进展及干预治疗中的肿瘤免疫微环境浸润肿瘤相关巨噬细胞的浸润密度和表型极化的动态检测方法，并建立了与预后的相关性，为肿瘤进展、预后监测及个体化治疗提供了新的策略；4）通过构建自钝化壳层新结构，发展了提高量子点近红外光学信号稳定性的新方法，为量子点探针应用于高灵敏动态可视化检测恶性生物学事件及生物体内可靠稳定标记奠定了重要的基础。本项目研究内容以肿瘤免疫微环境浸润巨噬细胞为靶标，为发展灵敏准确的肿瘤免疫微环境分子影像诊断技术及个体化治疗方案提供了新的思路，相关研究成果在Science Translational Medicine, J. Am. Chem. Soc, Angew. Chem. Int. Ed., ACS Nano, Biomaterials, Small, Adv. Healthcare Mater., Nanoscale等国际期刊发表研究论文20篇（IF>10，10篇），申请中国发明专利4项，培养博士毕业生5人。