乳腺癌是严重危害女性健康的杀手，临床不易察觉的隐匿性微小癌灶、转移灶和微小残留癌灶在术中难以被检测到，促使肿瘤发生复发和转移，是导致乳腺癌患者死亡的主要原因。因此，乳腺癌微小癌灶和转移灶的有效成像诊断是提高乳腺癌患者五年生存率的关键，是当前乳腺癌诊疗领域中重要的、亟待解决的科学问题之一。近年来兴起的近红外荧光成像技术凭借其高灵敏度、高特异性、低成本、易操作、无辐射等优点为解决上述难题带来了新契机，但如何开发成像性能优异的近红外探针仍然充满挑战。

本论文从目前乳腺癌微小癌灶及转移灶难以精准检测的临床问题以及可用于乳腺癌成像的近红外荧光探针开发难的科学问题出发，旨在利用肿瘤细胞代谢异常导致的肿瘤酸性微环境（肿瘤的细胞外pH 6.5 ‒ 7.0，健康组织中细胞外pH约为7.4）为激活源，开发高特异、高灵敏的新型智能化近红外荧光探针用于乳腺癌的精准成像，具体研究内容如下：

（1）代谢酸激活型磷酸钙荧光探针的精准调控及对乳腺癌的高特异性成像

针对乳腺癌微小癌灶成像检测难的问题，受磷酸溶液的三元平衡启发，我们通过改变合成过程中的体系pH值实现了对探针pH响应范围的精确调控，最终制备出响应范围完全匹配肿瘤微酸代谢环境的磷酸钙近红外荧光探针。该探针不仅能够区分正常组织和肿瘤微酸性微环境的细微差别，而且能够在非常窄的pH变化范围（pH 6.8 ‒ 7.0、ΔpH = 0.2）内快速实现荧光由“OFF”到“ON”的转变，从而清晰地区分肿瘤和正常组织。实验结果表明，所制备的探针在正常生理环境中具有稳定性高、生物安全性好的优点，能够对微小的乳腺肿瘤病变进行高灵敏可视化（T/N值约为10）。这一工作不仅为构建pH响应范围可调的肿瘤微酸环境响应型智能纳米探针提供了一种有效策略，而且为实现乳腺癌微小病灶的早期精准诊断提供了有益的参考。

（2）乳腺癌肺部转移瘤的特异性探针构建及高灵敏成像性能研究

针对乳腺癌易发生肺部转移且难以高灵敏成像检测的临床问题，我们在上一工作的基础上进一步优化了探针的合成条件，使探针的响应倍数提高至100倍，并成功地利用该探针实现了对单/多灶点乳腺癌肺部转移瘤及肺部原位瘤的高特异性、高灵敏性成像。该研究为针对肺部肿瘤病灶的在体精准检测提供了一个可行的范例。

（3）pH激活型纳米探针高特异高灵敏识别乳腺癌转移性淋巴结

针对目前临床乳腺癌术中前哨淋巴结示踪过程中，使用的ICG探针无法精准区分正常淋巴结和转移性淋巴结的问题，结合转移性淋巴结组织外具有弱酸性的特征，我们把ICG限域在磷酸钙内，构建了具有良好生物相容性和低免疫反应的肿瘤酸性微环境响应型近红外光学探针并在小鼠乳腺癌淋巴结转移瘤模型中考查了探针的在体成像性能。结果表明所制备的探针作为一种非侵入性pH可激活型造影剂，可精确区分正常淋巴结和转移性淋巴结。该研究拓展了激活型分子影像探针用于术中实时指导淋巴结检测的潜在应用。

本论文从肿瘤细胞特有的异常糖酵解特征入手，通过自组装策略以及对合成过程的有效调控成功构建了两种肿瘤代谢酸激活的磷酸钙基近红外荧光探针。得益于探针对肿瘤微酸代谢环境的超灵敏响应性能，所构建探针不仅能够对乳腺癌微小肿瘤进行高特异性成像，而且还能够对乳腺癌转移灶及转移淋巴结进行高灵敏可视化。这项研究为构建pH响应范围可调的智能化近红外荧光探针提供了一种有效的策略，有利于进一步推进该类探针在肿瘤的精准诊断与治疗方面的应用。

Breast cancer is one of the world’s leading causes of death, with low five-year survival rate, which is mainly due to missing the best timing of treatment and cancer metastasis in the clinical management. The precise diagnosis of tiny cancers and metastatic cancers from breast cancer greatly increases the chances of effective treatment and can help reduce further suffering and mortality. Advances in the near-infrared fluorescence imaging provide great opportunities for identifying cancer at its early stages and ultimately optimizing patient-specific therapies, owing to its considerable advantages over traditional molecular imaging, such as high signal-to-background ratio (SBR), high sensitivity, low cost.

The improvement of imaging sensitivity is crucial for the detection of tiny cancers and metastatic cancers. The improving of SBR is the key to gaining the higher sensitivity and realizing accurate tumor detection. It is an effective strategy to improve SBR by reducing the signal from non-tumor parts. Therefore, the design of activated near-infrared (NIR) fluorescent probes is more promising. Activatable probes are designed to stay in the “OFF” state in non-target tissues or blood, and signals can be turned “ON” only in response to specific targets or events. Consequently, elimination of the background signal dramatically improves the SBR, thereby making activatable probes a preferential choice for cancer imaging with high specificity and sensitivity. To design activatable probes for cancer detection, choosing a suitable stimulus plays a significant role in design. There is growing recognition that cancer is a metabolic disease. Although tumors are highly heterogeneous and complex, dysregulated energy metabolism is commonly observed in nearly all types of cancer cells. A potential target for imaging in breast cancers is acidic extracellular pH (pH 6.5 – 7.0), which mainly results from the abnormal aerobic glycolysis of tumor cells, has been recognized as a hallmark of different subtypes of breast cancers and metastatic tumors. Therefore, we aim to develop pH-activatable probes to targeting tiny breast tumors and metastatic tumors. The detailed works of dissertation are listed below.

(1) A metabolic acidity-activatable calcium phosphate probe with fluorescence signal amplification capabilities for non-invasive imaging of tiny breast tumors.

In this work, we report a robust strategy to create a metabolic acidity-activatable calcium phosphate (CaP) fluorescent probe (hereafter referred to as MACaP) based on the self-assembly of CaP and the NIR dye IR780 iodide mediated by a poly(acrylic acid) (PAA). By delicately modulating the synthesis conditions of the MACaP probe, its pH-responsive range could be adjusted to perfectly match the extracellular pH of the tumor microenvironment, with rapid and sharp responsiveness (pH range: 6.8 – 7.0, ΔpH = 0.2). The fluorescent probe remained silent in blood and normal tissue, owing to an aggregation-caused quenching (ACQ) effect (OFF state). However, upon reaching the tumor sites, the probe underwent fast disassembly in the acidic tumor pH range, which caused the release of IR780 and significantly enhanced the fluorescence signal (ON state), enabling tumor-specific imaging against a dark background. The MACaP probe benefited from its OFF/ON design and its ultra-pH sensitivity exhibited superior ability for in vivo tiny breast tumors imaging.

(2) An acidic-microenvironment activatable probe for ultrahigh specific fluorescence imaging of lung metastases.

We further optimized the synthetic conditions of the probe and obtained acidic-microenvironment activatable CaP fluorescent probe, SCaPI, with improved SBR value. Meanwhile, the superior sensitivity and specificity of SCaPI enabled high-contrast visualization of breast cancer with single/multiple lung metastases, as well as lung adenocarcinoma in situ.

(3) Sensitive and specific identification of sentinel lymph node metastasis using a pH-activatable probe.

In this work, we designed a tumor acidity-sensitive, NIR probe (termed ICPPs) for specific and sensitive identification of sentinel lymph nodes metastasis in vivo, based on calcium phosphate matrix and a NIR fluorophore, indocyanine green (ICG). We investigated the capability and sensitivity of this probe for tumor extracellular pH imaging in vitro and in vivo using metastatic sentinel lymph nodes model. Our results showed that the new probe provides non-invasive pH-activatable precise detect metastatic lymph nodes in vivo.

In summary, through a self-assembly strategy, as well as rational regulation of the preparation conditions, we successfully developed two pH-ultrasensitive CaP-based fluorescent probes. Unlike traditional CaP nanoprobes, which usually display broad pH responses inside endosomes or lysosomes at a low pH (4.0 – 6.0), probes could sharply respond to the subtle pH difference between the tumor microenvironment and normal tissues (pH 6.8 – 7.0, ΔpH = 0.2), leading to the activation of fluorescence for in vivo tumor imaging. Owing to its extreme sensitivity to the tumor extracellular pH, probes would not produce any noticeable fluorescence signal until reaching the tumor site, thereby significantly increasing the SBR. Our results demonstrated that probes could not only be used for imaging various tumors with high specificity but also enabled robust visualization of smaller tumor lesions and metastatic lesions. This study provides a robust strategy to modulate the pH response range of activatable NIR probes, which is particularly important for their applications in precise tumor diagnosis and treatment.

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