基于Fe掺杂多元复合金属纳米探针的靶向预定位系统构建及其针对乳腺癌血管生成拟态诊治一体的分子影像学研究

Vasculogenic mimicry（VM）refers to the plasticity of the aggressive breast cancer cells and establishes an adequate blood supply for tumor growth. VM is the major cause of the unsatisfactory outcome on anti-angiogenesis therapy. As a unique perfusion way, VM is associated with tumor metastasis and prognosis. However, few studies were aimed to investigate the non-invasive imaging strategies for accurate VM detection and treatment. Following on from our previous studies on the synthesis of copper antimony sulfide (Cu-Sb-S) as a single-phased ternary bimetal sulfide nanoparticles (NPs) for photoacoustic imaging (PAI), we innovatively design a novel theranostics platform based on Fe-doped Cu-Sb-S NPs for VM-targeted PAI/MRI bimodal image-guided photothermal therapy (PTT). We will characterize the magnetic properties and near-infrared optical absorbance of the nanomaterials. We will also investigate the use of the as-obtained NPs for the in vitro photothermal cancer treatment. With the aid of antibody guided pretargeting approach designed to specifically target over-expressed CD271 receptors on VM, spatially/timely selective damage of the VM structures by PTT will be conducted on breast cancer tumor bearing mouse model, and therapeutic response will be monitored by real-time PAI/MRI bimodal imaging. Independent of angiogenesis targeted strategies, our studies further encourage application of this VM-targeted PAI/MRI/PTT theranostics hypothesis for accurate detection, prognosis evaluation, and targeted therapy for breast cancer.

血管生成拟态（Vasculogenic Mimicry，VM）是乳腺癌内部通过肿瘤细胞变形获取血供的主要方式，亦是传统抗血管生成治疗效果不佳的重要原因，与其转移及预后密切相关。然而，目前尚缺少针对VM精准诊治的影像学手段。本研究在前期发现铜锑硫复合金属硫化物作为优异光声成像材料的基础上，提出在其中掺杂Fe元素构建多功能分子探针实现VM靶向光声成像/MRI/光热治疗的科学假说，拟表征分子探针的光吸收及磁学性能，评价其体外光热杀伤能力；建立荷乳腺癌裸鼠动物模型，以VM高表达CD271受体作为靶点，采用预定位系统引导分子探针在VM中特异性聚集，对其进行动态光声/MRI双模态成像研究；通过实时监测肿瘤微血管内分子探针的时间/空间分布信息，探索实施精准影像指导下的时空选择性光热治疗。区别于以往针对血管生成，本研究从VM诊疗一体化的新视点出发，旨在为乳腺癌的早期诊断、预后判断及靶向治疗提供新的途径。

本研究在前期发现铜锑硫复合金属硫化物作为优异光声成像材料的基础上，提出在其中掺杂Fe元素构建多功能分子探针实现乳腺癌靶向光声成像/MRI/光热治疗/化学动力治疗的科学假说，表征分子探针的理化性质、光吸收及磁学性能，证实分子探针具有较强的光吸收能力、光热转化性能和光热稳定性；通过CCK-8证实分子探针对正常乳腺成纤维细胞具有较好的生物相容性。体外实验证实分子探针可以催化H2O2产生羟基自由基（•OH），具有良好的CDT效果。通过乳腺癌4T1细胞与分子探针共孵育，使用近红外激光照射后，荧光探针DCFH-DA探针检测4T1细胞内活性氧显著增加，细胞活死实验证实其具有较强的光热杀伤能力。建立荷乳腺癌裸鼠动物模型，对其进行动态光声/MRI双模态成像研究，同时使用多波长PAI反映肿瘤区域的含氧血红蛋白浓度变化；通过实时监测肿瘤微血管内分子探针的时间/空间分布信息，实施精准影像指导下的时空选择性光热治疗。此外，Fe元素掺杂的分子探针能够触发CDT效应抑制肿瘤生长，并通过铁过载引发氧化脂质诱导肿瘤细胞激活铁死亡通路。本研究从诊疗一体化的新视点出发，旨在为乳腺癌的早期诊断、预后判断及靶向治疗提供新的途径。