Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario, 1151 Richmond Street, London, ON, N6A 3K7, Canada.
Department of Medical Biophysics, The University of Western Ontario, London, ON, N6A 3K7, Canada.
Invest New Drugs. 2019 Aug;37(4):595-601. doi: 10.1007/s10637-018-0644-3. Epub 2018 Aug 13.
The response of tumor intracellular pH to a pharmacological challenge could help identify aggressive cancer. Chemical exchange saturation transfer (CEST) is an MRI contrast mechanism that is dependent on intracellular pH (pH). pH is important in the maintenance of normal cell function and is normally maintained within a narrow range by the activity of transporters located at the plasma membrane. In cancer, changes in pH have been correlated with both cell proliferation and cell death. Quercetin is a bioflavonoid and monocarboxylate transporter (MCT) inhibitor. Since MCTs plays a significant role in maintaining pH balance in the tumor microenvironment, we hypothesized that systemically administered quercetin could selectively acidify brain tumors. The goals of the current study were to determine whether CEST MRI measurements sensitive to tumor pH could detect acidification after quercetin injection and to measure the magnitude of the pH change (ΔpH). Using a 9.4 T MRI, amine and amide concentration independent detection (AACID) CEST spectra were acquired in six mice approximately 15 ± 1 days after implanting 10 U87 human glioblastoma multiforme cells in the brain, before and after administration of quercetin (dose: 200 mg/kg) by intraperitoneal injection. Three additional mice were studied as controls and received only vehicle dimethyl sulfoxide (DMSO) injection. Repeated measures t-test was used to compare AACID changes in tumor and contralateral tissue regions of interest. Two hours after quercetin injection there was a significant increase in tumor AACID by 0.07 ± 0.03 corresponding to a 0.27 decrease in pH, and no change in AACID in contralateral tissue. There was also a small average increase in AACID in tumors within the three mice injected with DMSO only. The use of the natural compound quercetin in combination with pH weighted MRI represents a unique approach to cancer detection that does not require injection of an imaging contrast agent.
肿瘤细胞内 pH 值对药理挑战的反应有助于识别侵袭性癌症。化学交换饱和转移（CEST）是一种 MRI 对比机制，依赖于细胞内 pH 值（pH 值）。pH 值在维持正常细胞功能方面很重要，通常通过位于质膜上的转运体的活性在狭窄范围内维持。在癌症中，pH 值的变化与细胞增殖和细胞死亡都有关。槲皮素是一种生物类黄酮和单羧酸转运体（MCT）抑制剂。由于 MCT 在维持肿瘤微环境中的 pH 值平衡方面起着重要作用，我们假设系统给予槲皮素可以选择性地使脑肿瘤酸化。目前研究的目的是确定对肿瘤 pH 值敏感的 CEST MRI 测量是否可以检测到槲皮素注射后的酸化，并测量 pH 值变化的幅度（ΔpH）。使用 9.4T MRI，在大约植入脑内 10U87 人胶质母细胞瘤多形性细胞瘤细胞 15±1 天后，在腹腔注射槲皮素（剂量：200mg/kg）前后，在六只小鼠中获得了胺和酰胺浓度独立检测（AACID）CEST 谱。另外三只小鼠作为对照，仅接受载体二甲基亚砜（DMSO）注射。重复测量 t 检验用于比较肿瘤和对侧组织感兴趣区域的 AACID 变化。槲皮素注射后 2 小时，肿瘤 AACID 显著增加 0.07±0.03，对应 pH 值降低 0.27，对侧组织的 AACID 无变化。仅注射 DMSO 的三只小鼠的肿瘤内 AACID 也有平均轻度增加。天然化合物槲皮素与 pH 值加权 MRI 的结合使用代表了一种独特的癌症检测方法，不需要注射成像对比剂。
