Department of Radiology Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
Nanotheranostics. 2022 Feb 14;6(3):270-285. doi: 10.7150/ntno.64735. eCollection 2022.
Gas-core nanoscale bubbles (or nanobubbles) have gained significant recent attention as promising contrast agents for cancer molecular imaging using medical ultrasound. Previous work has shown that active targeting of nanobubbles to tumor biomarkers such as the prostate-specific membrane antigen (PSMA) significantly prolongs ultrasound signal enhancement, which is a critical feature for successful tumor diagnosis. However, the specific mechanism behind this effect is not well understood, and has not been previously studied in detail. Thus, in the current work, we investigated the process of PMSA- targeted nanobubble transport in tumors across different scales from whole tumor imaging using high-frequency dynamic contrast-enhanced ultrasound to intracellular confocal imaging and, molecularly using headspace gas chromatography/mass spectrometry. Data demonstrated that, indeed, molecular targeting of nanobubbles to the PSMA biomarker prolongs their tumor uptake and retention across the entire tumor volume, but with variability due to the expected tumor heterogeneity. Importantly, , the active targeting of NBs results in internalization via receptor-mediated endocytosis into the target cells, and the co-localization with intracellular vesicles (late-stage endosomes/lysosomes) significantly prolongs perfluorocarbon gas retention within the cells. This has not been directly observed previously. These results support the potential for nanobubbles to enable highly specific, background-free diagnostic imaging of the target cells/tissues using ultrasound.
气核纳米级气泡（或纳米气泡）作为医学超声用于癌症分子成像的有前途的对比剂，最近受到了广泛关注。以前的工作表明，主动靶向纳米气泡到肿瘤标志物，如前列腺特异性膜抗原（PSMA），显著延长超声信号增强，这是成功肿瘤诊断的关键特征。然而，这种效应背后的具体机制尚不清楚，以前也没有详细研究过。因此，在目前的工作中，我们从全肿瘤成像的高频动态对比增强超声到细胞内共聚焦成像，以及分子水平使用顶空气相色谱/质谱，研究了 PSMA 靶向纳米气泡在肿瘤中的传输过程。数据表明，纳米气泡确实通过 PSMA 标志物的分子靶向延长了它们在整个肿瘤体积中的摄取和保留，但由于预期的肿瘤异质性，存在变异性。重要的是，NB 的主动靶向导致通过受体介导的内吞作用进入靶细胞内化，并且与细胞内囊泡（晚期内体/溶酶体）的共定位显著延长了全氟碳气体在细胞内的保留。这以前没有直接观察到。这些结果支持了纳米气泡在使用超声进行高特异性、无背景的靶细胞/组织诊断成像的潜力。
