磷酸钙荧光探针：现形吧，肿瘤君！

论文概述

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导读

虽然肿瘤具有高度异质性, 但几乎在所有类型的肿瘤细胞中都普遍存在着代谢异常现象. 和正常组织的酸性相比(pH 7.2~7.4), 以异常糖酵解为特征的肿瘤细胞具有更低的细胞外酸性(pH 6.5~7.0), 为肿瘤的成像和治疗提供了一个潜在靶点. 然而绝大多数pH敏感的材料都表现出较宽的pH响应范围, 无法区分这种细微的pH差异. 在该研究中, 研究者通过对探针合成条件的精细调控构建了肿瘤代谢微酸激活的磷酸钙(CaP)荧光探针MACaP9.与传统的CaP纳米探针(通常在更低的pH值条件下(4.0~6.0)才具有响应性能)相比, MACaP9不仅能够被肿瘤微环境的pH特异性激活, 而且能够快速地将肿瘤微环境和正常组织之间的细微pH值差异(pH 6.8~7.0、ΔpH=0.2)转变成明显的荧光信号, 从而清晰地区分肿瘤和正常组织, 显著增加了在体成像时的信噪比. 研究结果表明, MACaP9不仅能够对各种类型的肿瘤进行高特异性成像, 而且还能够对微小的肿瘤病变进行高灵敏可视化.

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图文速览 

Figure 1  The schematic diagram of MACaP. (a) Schematic illustration of the construction of tumor metabolic acidity-activatable calcium phosphate probe system and (b) capability for precise tumor imaging.

Figure 2  Physicochemical characterization of MACaP. (a) pH variation of ionic concentrations in phosphoric acid solutions. (b) Thetriprotic equilibrium for phosphoric acid solutions. (c) Representative TEM images of MACaP9 at pH 7.4 (c₁) and pH 6.8 (c₂). Scalebar: 100 nm. (d) Elemental mapping image of MACaP9. Scale bar: 50 nm. (e) Absorption spectra and (f) fluorescence emission of IR780 (red), IR780/PAA/Ca (blue) and MACaP9 (black) during synthesis.

Figure 3  The pH-responsive properties of MACaP. (a) Absorption spectra and (b) fluorescence spectra of MACaP9 at pH 7.4 (black), 6.8 (red) and 4.5 (blue). (c) Normalized fluorescence intensity as a function of pH for MACaP probes fabricated at different pH values (pH = 8.0, 8.5, 9.0, 10.0, 11.0, 12.0, 13.0). (d) Normalized fluorescence intensity as a function of pH for MACaP9.

Figure 4  In vivo optical imaging. (a) Whole-body optical imaging of subcutaneous 4T1 tumor-bearing BALB/c nude mice at different time after injected with Always-ON IR780 (above) or OFF-ON MACaP9 probe (below). (b) T/N ratio as a function of time (n = 5) from (a). (c) Ex vivo fluorescence imaging of tumor and major organs (liver, kidney, lung, spleen) at 6 h post-injection of Always-ON or OFF-ON probe.

Figure 5  The specificity of MACaP9 for tumor extracellular pH-responsive imaging. (a) Schematic diagram of the activation process of MACaP9 and aerobic glycolysis converts glucose to lactate in cancer cells. 2-DG is a metabolic inhibitor for glucose uptake. CHC is a metabolic inhibitor for preventing the transport of lactic acid outside the cell. NaHCO₃ as an acid neutralizer (GLUT: glucose transporter; MCT: monocarboxylate transporter). Immumofluorescence staining and immunohistochemical staining of (b) MCT4 and (c) LDH-A. Scale bar: 50 μm. (d) Whole-body optical imaging of subcutaneous 4T1 tumor-bearing BALB/c nude miceat different time after intravenous injection of MACaP9. For comparison, metabolic inhibitor (2-DG or CHC) and NaHCO₃ was respectively intratumorally administered to tumor for 12 h before the intravenous injectionof MACaP9.

Figure 6  The tumor imaging performance of MACaP9 in different tumor models. (a) Whole-body optical imaging of subcutaneous tumor models of different cancer types (A549, HepG2, PC-3, MCF-7, SGC-7901) and orthotopic glioma-bearing BALB/c nude mice at different time after injected with MACaP9. (b) Representative H&E staining images of tumor tissues excised from the mice at 12 h post-injection of MACaP9. Scale bar: 50 μm. (c) Whole-body optical imaging of mice bearing 4T1 tumors with different size after intravenous injection of MACaP9 at different time. (d) H&E staining images of different tumor tissues excised from the mice at 12 h post-injection of MACaP9. Scale bar: 100 μm.

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文章信息 

Qian Jia, Ruili Zhang, Yongdong Wang, Haohao Yan, Zheng Li, Yanbin Feng, Yu Ji, Zuo Yang, Yang Yang, Kanyi Pu, Zhongliang Wang. A metabolic acidity-activatable calcium phosphate probe with fluorescence signal amplification capabilities for non-invasive imaging of tumor malignancy. Science Bulletin, 2022, 67(3): 288–298, doi: 10.1016/j.scib.2021.11.003

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