Targeting Acidity in Pancreatic Adenocarcinoma: Multispectral Optoacoustic Tomography Detects pH-Low Insertion Peptide Probes In Vivo.
Targeting Acidity in Pancreatic Adenocarcinoma: Multispectral Optoacoustic Tomography Detects pH-Low Insertion Peptide Probes In Vivo.
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DOI：
10.1158/1078-0432.ccr-15-0314
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发表时间：
2015-10-15
期刊：
影响因子：
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通讯作者：
McNally LR
中科院分区：
文献类型：
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作者：
Kimbrough CW;Khanal A;Zeiderman M;Khanal BR;Burton NC;McMasters KM;Vickers SM;Grizzle WE;McNally LR
pH 低插入肽 (pHLIP) 可作为靶向部分，使 pH 敏感探针能够检测实体瘤。将这些探头与多光谱光声断层扫描 (MSOT) 结合使用是改善胰腺癌成像的一种有前途的方法。 pH 敏感的 pHLIP (V7) 与 750 NIR 荧光染料缀合，并作为胰腺腺癌的靶向探针进行评估。 pH 不敏感的 K7 pHLIP 作为非目标对照。使用人胰腺细胞系 S2VP10 和 S2013 在 pH 7.4、6.8 和 6.6 下体外评估探针结合。然后使用 MSOT，用小鼠原位胰腺腺癌模型在体内评估半定量探针积累。在体外，与 pH 7.4 相比，V7-750 探针在 pH 6.6 下表现出明显更高的荧光（S2VP10，p=0.0119；S2013，p=0.0160），而与 K7-750 对照没有观察到差异（S2VP10，p=0.8783；S2013，p=0.921）。在体内 S2VP10 模型中，V7-750 探针产生 782.5 MSOT a.u。信号与 5.3 MSOT a.u. 相比肿瘤中的 K7-750 对照 (p= 0.0001)。同样，V7-750 探针信号为 578.3 MSOT a.u。在 S2013 模型中与 5.1 MSOT a.u 的 K7-750 信号相比（p=0.0005）。 V7-750 探针在肝脏或肾脏内的脱靶积累极少，并且通过离体成像证实了探针的分布。与 pH 不敏感对照相比，V7-750 pH 敏感探针专门针对胰腺腺癌，并且具有最小的脱靶积累。通过 MSOT 对 pH 靶向探针进行非侵入性检测是改善胰腺癌检测和监测的一种有前景的方法。
pH-low Insertion Peptides (pHLIPs) can serve as a targeting moiety that enables pH-sensitive probes to detect solid tumors. Using these probes in conjunction with multispectral optoacoustic tomography (MSOT) is a promising approach to improve imaging for pancreatic cancer. A pH-sensitive pHLIP (V7) was conjugated to 750 NIR fluorescent dye and evaluated as a targeted probe for pancreatic adenocarcinoma. The pH-insensitive K7 pHLIP served as an untargeted control. Probe binding was assessed in vitro at pH 7.4, 6.8, and 6.6 using human pancreatic cell lines S2VP10 and S2013. Using MSOT, semi-quantitative probe accumulation was then assessed in vivo with a murine orthotopic pancreatic adenocarcinoma model. In vitro, the V7–750 probe demonstrated significantly higher fluorescence at pH 6.6 compared to pH 7.4 (S2VP10, p=0.0119; S2013, p=0.0160), while no difference was observed with the K7–750 control (S2VP10, p=0.8783; S2013, p=0.921). In the in vivo S2VP10 model, V7–750 probe resulted in 782.5 MSOT a.u. signal compared to 5.3 MSOT a.u. in K7–750 control in tumor (p= 0.0001). Similarly, V7–750 probe signal was 578.3 MSOT a.u. in the S2013 model compared to K7–750 signal at 5.1 MSOT a.u. (p=0.0005). There was minimal off-target accumulation of the V7–750 probe within the liver or kidney, and probe distribution was confirmed with ex vivo imaging. Compared to pH-insensitive controls, V7–750 pH-sensitive probe specifically targets pancreatic adenocarcinoma, and has minimal off-target accumulation. The non-invasive detection of pH-targeted probes by means of MSOT represents a promising modality to improve the detection and monitoring of pancreatic cancer.