Lu Kang, Zhang Mengxi, Tian Zuotong, Xiao Han
Department of Chemistry, Rice University 6100 Main Street Houston TX 77005 USA
SynthX Center, Rice University 6100 Main Street Houston TX 77005 USA.
RSC Chem Biol. 2025 Mar 14;6(5):754-760. doi: 10.1039/d4cb00310a. eCollection 2025 May 8.
Bone metastasis is a leading cause of mortality in breast cancer patients. Monitoring biomarkers for bone metastasis in breast cancer is crucial for the development of effective interventional treatments. Despite being a highly vascularized tissue, the bone presents a particularly hypoxic environment. Tumor hypoxia is closely linked to increased levels of various reductases, including nitroreductase (NTR). Currently, there are few probes available to detect NTR levels in breast cancer bone metastases. Although bioluminescent imaging is promising due to its specificity and high signal-to-noise ratio, many probes face challenges such as short emission wavelengths, reliance on complex conditions like external adenosine triphosphate, or lack of tissue specificity. In this study, through "caging" the luciferase substrate with an NTR-responsive aromatic nitro recognition group, we developed a highly sensitive and selective NTR-sensitive bioluminescent probe. The resulting probe effectively detects NTR in breast cancer cells and enables real-time monitoring of NTR in a mouse model of breast cancer bone metastasis. Additionally, it can differentiate between primary and bone tumors, and allow continuous monitoring of NTR levels, thus providing valuable insights into bone tumor progression. This work provides a powerful tool for further understanding the biological functions of NTR in breast cancer bone metastasis.
骨转移是乳腺癌患者死亡的主要原因。监测乳腺癌骨转移的生物标志物对于开发有效的介入治疗至关重要。尽管骨骼是高度血管化的组织，但其呈现出特别缺氧的环境。肿瘤缺氧与包括硝基还原酶（NTR）在内的各种还原酶水平升高密切相关。目前，可用于检测乳腺癌骨转移中NTR水平的探针很少。虽然生物发光成像因其特异性和高信噪比而具有前景，但许多探针面临诸如发射波长较短、依赖外部三磷酸腺苷等复杂条件或缺乏组织特异性等挑战。在本研究中，通过用NTR响应性芳香硝基识别基团“笼蔽”荧光素酶底物，我们开发了一种高度灵敏且选择性的NTR敏感生物发光探针。所得探针可有效检测乳腺癌细胞中的NTR，并能够在乳腺癌骨转移小鼠模型中实时监测NTR。此外，它可以区分原发性肿瘤和骨肿瘤，并允许连续监测NTR水平，从而为骨肿瘤进展提供有价值的见解。这项工作为进一步了解NTR在乳腺癌骨转移中的生物学功能提供了一个强大的工具。
