Purpose

Noninvasive detection of high-risk plaques is still challenging. In this study, we aimed to noninvasively assess αvβ3-integrin expression using a customed photoacoustic (PA) computed tomography (PACT)/ultrasound (US) system in atherosclerotic lesions of varying degrees of severity and to explore its potential value for detecting high-risk plaques.

Methods

We constructed αvβ3-integrin-targeted ultrasmall gold nanorods (AuNRs) with cyclo Arg-Gly-Asp (cRGD) and tested their properties. Employing C57BL/6 J (wild-type, WT) mice and apolipoprotein E gene knockout (ApoE^−/−) mice fed either a chow diet or a high-fat/high-cholesterol diet (HFHCD), we established varying degrees of lesion severity. In vivo PACT/US imaging was performed to assess αvβ3-integrin expression in the 4 groups by cRGD-AuNRs. Further histopathologic examination was conducted to evaluate the plaque vulnerability indicators.

Results

The data showed that cRGD-AuNRs exhibited excellent photothermal conversion capacity, stability, targeting ability, and biocompatibility. The immunohistochemical results indicated that αvβ3-integrin was upregulated with increasing aggravation of the lesions. In vivo PACT/US imaging showed good consistency with αvβ3-integrin expression. Notably, ApoE^−/− mice fed a HFHCD showed an abrupt PA intensity increase compared with the other groups. The histopathologic examination verified that the atherosclerotic plaques of ApoE^−/− mice fed the HFHCD developed unstable phenotypes. Correlation analysis showed that PA intensity was mainly related to inflammation and angiogenesis among all of the indicators.

Conclusion

Our data indicated that αvβ3-integrin is an effective indicator of plaque instability, and noninvasive PACT/US molecular imaging assessment of αvβ3-integrin holds promise in detecting high-risk plaques.

中文翻译：

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无创光声计算机断层扫描/超声成像识别高风险动脉粥样硬化斑块

目的

高危斑块的无创检测仍然具有挑战性。在这项研究中，我们旨在使用定制的光声 (PA) 计算机断层扫描 (PACT)/超声 (US) 系统在不同严重程度的动脉粥样硬化病变中无创评估 αvβ3-整合素表达，并探索其检测高危动脉粥样硬化的潜在价值斑块。

方法

我们构建了具有环 Arg-Gly-Asp (cRGD) 的 αvβ3-整合素靶向超小型金纳米棒 (AuNR) 并测试了它们的特性。使用 C57BL/6 J（野生型，WT）小鼠和载脂蛋白 E 基因敲除（ApoE ^−/−）小鼠喂食食物或高脂肪/高胆固醇饮食 (HFHCD)，我们建立了不同程度的损伤严重性。通过 cRGD-AuNRs 进行体内 PACT/US 成像以评估 4 组中的 αvβ3-整合素表达。进行进一步的组织病理学检查以评估斑块易损性指标。

结果

数据表明，cRGD-AuNRs 表现出优异的光热转换能力、稳定性、靶向能力和生物相容性。免疫组织化学结果表明，αvβ3-整合素随着病变的加重而上调。体内 PACT/US 成像显示与 αvβ3-整合素表达具有良好的一致性。值得注意的是，与其他组相比，喂食 HFHCD 的 ApoE ^-/-小鼠表现出突然的 PA 强度增加。组织病理学检查证实，喂食 HFHCD的 ApoE ^{-/-小鼠的动脉粥样硬化斑块发展出不稳定的表型。}相关性分析表明，PA强度在所有指标中主要与炎症和血管生成有关。

结论

我们的数据表明，αvβ3-整合素是斑块不稳定性的有效指标，αvβ3-整合素的无创 PACT/US 分子影像学评估在检测高风险斑块方面具有前景。