Extracellular pH is important in clinical measurements due to its correlation to cell metabolism and disease progression. In MRI, T₁/T₂ ratiometric analysis and other methods have been previously applied to quantify pH using conventional pulse sequences. However, for nanoparticle-based approaches, heterogeneity in size and surface functionalization tends toward qualitative rather than quantitative results. To address this limitation, we developed a novel DNA-based MRI contrast agent, pH-DMRCA, which utilizes a highly programmable and reproducible nanostructure. The pH-DMRCA is a dendritic DNA scaffold that is functionalized with a pH-responsive MRI-sensitive construct, Gd(NP-DO3A), at the end of each DNA arm. We first evaluated the r₁ and r₂ response of our pH-DMRCA over a range of pH values (pH = 5–9) to establish a relaxometric model of pH. These MRI-based assessments of pH were validated in a separate set of samples using a pH electrode (n = 18) and resulted in a good linear correlation (R² = 0.99, slope = 0.98, intercept = 0). A Bland–Altman analysis of the results also showed reasonable agreement between the calculated pH and measured pH. Moreover, these pH comparisons were consistent across three different pH-DMRCA concentrations, demonstrating concentration-independence of the method. This MRI-based pH quantification methodology was further verified in human blood plasma. Given the versatility of the DNA-based nanostructures, the contrast agent has a potential to be applied to a wide variety of imaging applications where extracellular pH is important including cancer, stroke, cardiovascular disease, and other important diseases.

中文翻译：

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用于定量 p​​H 测量的基于 DNA 的 MRI 造影剂

细胞外 pH 值在临床测量中很重要，因为它与细胞代谢和疾病进展有关。在 MRI 中，T ₁ / T ₂比率分析和其他方法以前已用于使用常规脉冲序列量化 pH 值。然而，对于基于纳米颗粒的方法，尺寸和表面功能化的异质性倾向于定性而不是定量的结果。为了解决这一限制，我们开发了一种新型的基于 DNA 的 MRI 造影剂 pH-DMRCA，它利用高度可编程和可重复的纳米结构。pH-DMRCA 是一种树突状 DNA 支架，在每个 DNA 臂的末端用 pH 响应性 MRI 敏感结构 Gd(NP-DO3A) 进行功能化。我们首先评估了r我们的 pH-DMRCA 在一系列 pH 值（pH = 5-9）上的₁和r _{2响应，以建立 pH 的弛豫模型。}这些基于 MRI 的 pH 评估在使用 pH 电极 ( n = 18) 的一组单独样品中进行了验证，并产生了良好的线性相关性 ( R ²= 0.99，斜率 = 0.98，截距 = 0)。对结果的 Bland-Altman 分析也表明计算的 pH 值和测量的 pH 值之间存在合理的一致性。此外，这些 pH 比较在三种不同的 pH-DMRCA 浓度下是一致的，表明该方法与浓度无关。这种基于 MRI 的 pH 量化方法在人血浆中得到了进一步验证。鉴于基于 DNA 的纳米结构的多功能性，造影剂有可能应用于细胞外 pH 值很重要的各种成像应用，包括癌症、中风、心血管疾病和其他重要疾病。