Department of Chemistry and Beckman Institute for Advanced Science and Technology , University of Illinois at Urbana-Champaign , Urbana , Illinois 61801 , United States.
School of Pharmacy, Institutes of Integrative Medicine , Fudan University , Shanghai , 201203 , P. R. China.
J Am Chem Soc. 2019 Nov 6;141(44):17601-17609. doi: 10.1021/jacs.9b06694. Epub 2019 Oct 29.
Photoacoustic (PA) dyes, which absorb near-infrared (NIR) light to generate an ultrasonic signal, can be detected at centimeter depths in tissues with significantly higher resolution than dyes imaged with fluorescence-based methods. As such, PA agents show great promise as research tools for the study of live-animal disease models. However, the development of activatable PA probes has been hampered by the relative scarcity of appropriate PA-active molecular platforms with properties that can be manipulated in a rational manner. Herein we synthesized and evaluated six modifications to the aza-BODIPY dye platform with respect to their absorbance, fluorescence, and PA properties. We identified a promising onformationally estricted za-ODIPY (CRaB) scaffold that prioritizes three criteria necessary for the design of stimulus-responsive dyes with optimal ratiometric PA response: absorbance at NIR wavelengths, strong PA intensity, and large Δλ upon interaction with the desired stimulus. Using this scaffold, we synthesized three chemically diverse stimulus-responsive PA probes and demonstrated between 2- and 8-fold improvements in theoretical ratiometric response in vitro. This suggests that improvements in PA parameters are generalizable. Finally, we validated the in vitro turnover of each CRaB PA probe and demonstrated the in vivo potential of the CRaB scaffold by direct comparison to an established hypoxia-responsive probe for the detection of tumor hypoxia.
光声（PA）染料吸收近红外（NIR）光以产生超声信号，可在组织中检测到厘米深的位置，其分辨率明显高于荧光成像方法所成的像。因此，PA 试剂作为活体动物疾病模型研究工具具有很大的应用前景。然而，由于具有适当的 PA 活性的分子平台相对稀缺，并且其性质难以以合理的方式进行操纵，因此可激活的 PA 探针的开发受到阻碍。在此，我们合成并评估了 aza-BODIPY 染料平台的六种修饰物，分别针对其吸光度、荧光和 PA 特性。我们确定了一种有前途的受限构象 aza-ODIPY（CRaB）支架，该支架优先考虑了设计具有最佳比率响应 PA 响应的刺激响应染料所需的三个标准：NIR 波长的吸光度、较强的 PA 强度以及与所需刺激相互作用时的大Δλ。使用该支架，我们合成了三种化学性质不同的刺激响应 PA 探针，并在体外证明了理论比率响应提高了 2 至 8 倍。这表明 PA 参数的改进是普遍的。最后，我们验证了每个 CRaB PA 探针的体外周转率，并通过与用于检测肿瘤缺氧的已建立的缺氧响应探针进行直接比较，证明了 CRaB 支架在体内的潜力。
