Understanding the pharmacological properties of a metabolic PET tracer in prostate cancer
Understanding the pharmacological properties of a metabolic PET tracer in prostate cancer
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DOI：
10.1073/pnas.1405240111
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发表时间：
2014-05-20
影响因子：
11.1
通讯作者：
Lewis, Jason S.
中科院分区：
文献类型：
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作者：
Viola-Villegas, Nerissa Therese;Carlin, Sean D.;Lewis, Jason S.
一般来说，实体瘤（>400 mm（3））本身是酸性的，更具侵略性的生长产生更大的酸度。如果酸度可以作为生物标志物，它将提供一种衡量肿瘤生长速度和侵袭程度的方法，并为预测对pH依赖性化疗的反应提供基础。我们已经开发了一种Cu-64 pH（低）插入肽（pHLIP），用于通过PET靶向、成像和定量酸性肿瘤，我们的研究结果揭示了评估前列腺肿瘤的实用性。新的pHLIP版本限制了不加选择的健康组织结合，我们证明了它在三种不同的前列腺癌模型中靶向细胞外酸化，每种模型都具有不同的血管化和酸挤出蛋白碳酸酐酶IX（CAIX）表达。然后，我们描述了这种放射性示踪剂离体的肿瘤分布，与血液灌注和已知的生物标志物的酸度，如缺氧，乳酸脱氢酶A，和CAIX。我们发现，探针揭示了肿瘤之间和肿瘤内的代谢变化，并区分坏死和活肿瘤区域。
Generally, solid tumors (>400 mm(3)) are inherently acidic, with more aggressive growth producing greater acidity. If the acidity could be targeted as a biomarker, it would provide a means to gauge the pace of tumor growth and degree of invasiveness, as well as providing a basis for predicting responses to pH-dependent chemotherapies. We have developed a Cu-64 pH (low) insertion peptide (pHLIP) for targeting, imaging, and quantifying acidic tumors by PET, and our findings reveal utility in assessing prostate tumors. The new pHLIP version limits indiscriminate healthy tissue binding, and we demonstrate its targeting of extracellular acidification in three different prostate cancer models, each with different vascularization and acid-extruding protein carbonic anhydrase IX (CAIX) expression. We then describe the tumor distribution of this radiotracer ex vivo, in association with blood perfusion and known biomarkers of acidity, such as hypoxia, lactate dehydrogenase A, and CAIX. We find that the probe reveals metabolic variations between and within tumors, and discriminates between necrotic and living tumor areas.