Ashi Khalid H, Karmacharya Mrigendra B, Sultan Laith R, Guerrero David T, Chorny Michael, Sehgal Chandra M
Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
Department of Pediatrics, The Children's Hospital of Philadelphia/Perelman School of Medicine, Philadelphia, PA, USA.
IEEE Int Ultrason Symp. 2023 Sep;2023. doi: 10.1109/ius51837.2023.10307871. Epub 2023 Nov 7.
Vascular hyperpermeability (VHP), an abnormal increase in the leakiness of the blood vessels, is common in many diseases and disorders, including cancer, infections, and inflammation, among others. This study aims to develop a real-time, non-ionizing photoacoustic method for imaging and quantitative analysis of vascular hyperpermeability. Toward this goal, we investigate the use of Evans blue (EB) as a marker of VHP. The hypothesis is that photoacoustic imaging (PAI) of EB's high-molecular-weight complex with serum albumin can allow a non-invasive, robust, and specific analysis of VHP.
The studies were performed in mice with hepatocellular carcinoma implanted on both legs. Each animal acted as its control (microbubbles only), where ultrasound treatment induced hyperpermeability in one leg. PAI of HCC was performed before and after inducing hyperpermeability with ultrasound. The treatments included ultrasound alone and antivascular ultrasound (AVUS), combining ultrasound and microbubbles. The PA signal was unmixed for EB. The change in EB signal (ΔPA) induced by AVUS was compared with the treatment with ultrasound alone and a control group with no treatment. The image-derived PA measurements were compared with the Miles assay and histology performed on excised tumors.
PAI of the control group showed no difference in ΔPA between treated and untreated tumors: 0.14 ± 0.04 au versus 0.15 ± 0.07 au. The ultrasound-only group showed a small increase in ΔPA between the treated and the untreated groups: 0.14 ± 0.04 versus 0.18 ± 0.05. In contrast, the AVUS group showed a marked increase in ΔPA between the untreated and the treated groups: 0.18 ± 0.02 au versus 0.60 ± 0.19 au. EB concentration measured by Miles assay was highest in the AVUS group: 141 ± 48 ng/mg tissue compared to 61 ± 16 ng/mg tissue and 58 ± 24 ng/mg tissue in the ultrasound-only and the control group. Histology showed vascular dilation, vascular disruption, and extravasation of EB in the AVUS-treated group.
PAI is a promising platform for imaging and quantitative assessment of VHP. Future studies observing a temporal change in EB signal could provide a platform for quantitative permeability assessment in various diseases.
血管通透性增加（VHP）是指血管渗漏性异常升高，在包括癌症、感染和炎症等多种疾病和病症中很常见。本研究旨在开发一种用于血管通透性增加成像和定量分析的实时、非电离光声方法。为实现这一目标，我们研究了使用伊文思蓝（EB）作为VHP的标志物。假设是EB与血清白蛋白的高分子量复合物的光声成像（PAI）能够对VHP进行非侵入性、可靠且特异的分析。
研究在双腿植入肝细胞癌的小鼠身上进行。每只动物自身作为对照（仅微泡），其中超声治疗在一条腿上诱导了通透性增加。在用超声诱导通透性增加前后对肝癌进行PAI。治疗包括单独超声和抗血管超声（AVUS，超声与微泡联合）。对EB的光声信号进行解混。将AVUS诱导的EB信号变化（ΔPA）与单独超声治疗组和未治疗的对照组进行比较。将图像衍生的PA测量值与对切除肿瘤进行的迈尔斯试验和组织学结果进行比较。
对照组的PAI显示，治疗组和未治疗组之间的ΔPA无差异：分别为0.14±0.04任意单位（au）和0.15±0.07 au。仅超声组显示治疗组和未治疗组之间的ΔPA有小幅增加：分别为0.14±0.04和0.18±0.05。相比之下，AVUS组显示未治疗组和治疗组之间的ΔPA有显著增加：分别为0.18±0.02 au和0.60±0.19 au。通过迈尔斯试验测量的EB浓度在AVUS组中最高：为141±48纳克/毫克组织，而仅超声组和对照组分别为61±16纳克/毫克组织和58±24纳克/毫克组织。组织学显示AVUS治疗组有血管扩张、血管破坏和EB外渗。
PAI是用于VHP成像和定量评估的有前景的平台。未来观察EB信号随时间变化的研究可为各种疾病的定量通透性评估提供一个平台。
