Center for Theragnosis, Korea Institute of Science and Technology (KIST) , 39-1, Hawolgok-dong, Sungbuk-gu, Seoul 136-791, Korea.
Department of Chemistry Yonsei University , 50 Yonsei-ro, Seodaemungu, Seoul 120-749, Korea.
ACS Nano. 2015 Oct 27;9(10):9906-11. doi: 10.1021/acsnano.5b03377. Epub 2015 Sep 3.
Sensitive imaging of inflammation with a background-free chemiluminescence (CL) signal has great potential as a clinically relevant way of early diagnosis for various inflammatory diseases. However, to date, its feasibility has been limitedly demonstrated in vivo with locally induced inflammation models by in situ injection of CL probes. To enable systemic disease targeting and imaging by intravenous administration of CL probes, hurdles need to be overcome such as weak CL emission, short glowing duration, or inability of long blood circulation. Here, we report a CL nanoprobe (BioNT) that surmounted such limitations to perform precise identification of inflammation by systemic self-delivery to the pathological tissues. This BioNT probe was engineered by physical nanointegration of multiple kinds of functional molecules into the ultrafine nanoreactor structure (∼15 nm in size) that combines solid-state fluorescence-induced enhanced peroxalate CL and built-in machinery to control the intraparticle kinetics of CL reaction. Upon intravenous injection into a normal mouse, BioNT showed facile blood circulation and generated a self-lighted strong CL torchlight throughout the whole body owing to the tiny colloidal structure with an antifouling surface as well as high CL sensitivity toward endogenous biological hydrogen peroxide (H2O2). In mouse models of local and systemic inflammations, blood-injected BioNT visualized precise locations of inflamed tissues with dual selectivity (selective probe accumulation and selective CL reaction with H2O2 overproduced by inflammation). Even a tumor model that demands a long blood circulation time for targeting (>3 h) could be accurately identified by persistent signaling from the kinetics-tailored BioNT with a 65-fold slowed CL decay rate. We also show that BioNT exhibits no apparent toxicity, thus holding potential for high-contrast diagnostic imaging.
利用背景无干扰的化学发光（CL）信号进行敏感的炎症成像，作为各种炎症性疾病的早期诊断的一种具有临床相关性的方法，具有很大的潜力。然而，迄今为止，通过原位注射 CL 探针，在局部诱导的炎症模型中，其在体内的可行性受到限制。为了通过静脉内给予 CL 探针实现系统性疾病靶向和成像，需要克服一些障碍，例如 CL 发射较弱、发光持续时间短或无法进行长血液循环。在这里，我们报告了一种 CL 纳米探针（BioNT），它克服了这些限制，通过系统自身递送至病理组织，实现了炎症的精确识别。这种 BioNT 探针是通过将多种功能分子物理纳米集成到超细微纳米反应器结构中（尺寸约为 15nm）而构建的，该结构结合了固态荧光诱导增强过氧酸盐 CL 和内置机制来控制 CL 反应的颗粒内动力学。将 BioNT 经静脉注射入正常小鼠后，由于具有防污表面的微小胶体结构以及对内源性生物过氧化氢（H2O2）的高 CL 敏感性，BioNT 易于血液循环，并在全身产生自发光的强 CL 火炬。在局部和系统性炎症的小鼠模型中，血液注射的 BioNT 以双重选择性（通过炎症引起的 H2O2 过表达，实现探针的选择性积累和选择性 CL 反应）可视化了炎症组织的精确位置。即使是需要长时间（>3 小时）血液循环时间进行靶向的肿瘤模型，也可以通过动力学调整的 BioNT 的持续信号来准确识别，其 CL 衰减率减缓了 65 倍。我们还表明，BioNT 没有明显的毒性，因此具有高对比度诊断成像的潜力。
