Molecular Chemiluminescent Probes with a Very Long Near‐Infrared Emission Wavelength for in Vivo Imaging

Abstract

Chemiluminescence imaging is imperative for diagnostics and imaging due to its intrinsically high sensitivity. To improve in vivo detection of biomarkers, chemiluminophores that simultaneously possess near‐infrared (NIR) emission and modular structures amenable to construction of activatable probes are highly desired; however, these are rare. Herein, we report two chemiluminophores with record long NIR emission (>750 nm) via integration of dicyanomethylene‐4H‐benzothiopyran or dicyanomethylene‐4H‐benzoselenopyran with dioxetane unit. Caging of the chemiluminophores with different cleavable moieties produces NIR chemiluminescence probes (NCPs) that only produce signals upon reaction with reactive oxygen species or enzymes, for example, β‐galactosidase, with a tissue‐penetration depth of up to 2 cm. Thus, this study provides NIR chemiluminescence molecular scaffolds applicable for in vivo turn‐on imaging of versatile biomarkers in deep tissues.

A General Approach to Convert Hemicyanine Dyes into Highly Optimized Photoacoustic Scaffolds for Analyte Sensing**

“…The design of PA‐HD is based on the premise that sulfur‐substitution can potentially red‐shift the λ abs value by up to 50 nm and thus, can facilitate deeper tissue imaging and ratiometric calibration. A similar approach was recently employed to red‐shift chemiluminescent probes via sulfur‐substitution [20] . Moreover, we anticipate two additional benefits from this modification that favor photoacoustic imaging.…”

Stimuli Responsive Nitric Oxide-Based Nanomedicine for Synergistic Therapy

“…Although many advances have been achieved in the UV-vis light-triggered NO releasing system, the low tissue penetration and high phototoxicity of UV-vis light limit its application in the field of anti-tumor therapy [118]. Compared with UV-vis light, NIR light has become an emerging hotspot because of its high tissue penetration and low photoxicity [53,[119][120][121]. NIR can not only stimulate the release of NO from photo-sensitive NO donors but also mediate the role of photosensitizers in phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT) [81,122,123].…”

Emerging microfluidic chips on medical application

“…，⼜称芯⽚实验室(Lab-on-a Chip)或者⽣物芯⽚。微流控技术 [2] 由微 机电加⼯系统(Micro-Electro-Mechanical System，MEMS)发展⽽来，它是⼀种在微⽶级微管 [3] 中精确操纵 [4] 微量流体的技术⼿段，具有将⽣物、化学等实验室微缩到⼀个⼏平⽅厘⽶芯⽚中的基本功能(样品的制备、 分离、反应、检测等)。随着材料科学的发展，作为微流控芯⽚载体的材料也层出不穷，从硅、玻璃到纸基 [5] 、 ⽔凝胶 [6] 以及各类聚合物和纳⽶材料 [7,8] 。与此同时，微流控芯⽚的制备技术也蓬勃发展如丝⽹印刷，喷墨打 印、3D 打印 [9]， [10] 等，⼀些⾼精尖的加⼯技术如⻜秒激光加⼯技术、双光⼦ 3D 打印技术也为⾼精密度的微流 控芯⽚的制作提供了更多可能性。 微流控芯⽚有着微型化、⾼灵敏度、⾼集成、⾼通量、反应快、检测时间短等技术优势，在⽣物医学研 究，合成分析 [11] ，司法鉴定等众多领域有着⼴泛的应⽤(可穿戴微流控设备 [12] 、体外医疗诊断 [13] 、仿⽣⽪肤 [14] 组织器官 [15] ，⽣化 [16] 与环境分析、单细胞分析 [17] 、核酸分析、药物筛选递送 [18] )。迄今为⽌，微型化、集成 化和智能化已经成为现代科技⼿段的⼀个重要趋势，在这样的⼤环境下微流控芯⽚的发展⼗分迅速，它的分 类⽅法丰富多样，可根据不同的分析检测⽅法可以将微流控芯⽚分为电化学检测法 [19] 、光谱分析法(核磁共 振 [20] 、化学发光分析法 [21] )、⾮标记检测法 [22] ，分离富集 [8] 等。 微流控芯⽚是医学领域新⼀代床旁诊断(Point of care testing,POCT) [23,24] 主流技术。POCT 可直接在被检 者身边提供快捷有效的⽣化指标，现场指导⽤药，使检测、诊断、治疗成为⼀个连续过程，对于疾病的早期 发现和治疗具有突破性的意义。基于微流控芯⽚技术的 POCT 仪器发展趋势是⼩型化、操作便捷，直接输⼊ 体液样本 [25] ，即可迅速得到诊断结果 [26] ，由医⽣指导⽤药。⽬前，市场上有多种即时诊断⽅法，仅有简单地 流动测试⼯作没有流体管理技术，⽽当测试复杂性增加时，微流控技术是⼀⻔不可或缺的技术。在治疗肿瘤 癌症的医疗领域⽅⾯，微流控技术同样⼤放异彩，如何使药物特异性杀死肿瘤细胞⽽不伤害正常细胞，这⼀ 直是个业界难题，代尔夫特理⼯⼤学 Jan H. van Esch 的课题组 [27] 将微流控设备中搭载⼀种具有双重功能的新 ⽉形微凝胶，研究发现这些微凝胶对肺癌细胞有⾼亲和、⾼选择性，可以达到肺癌化疗的效果并且减轻副作 ⽤对⼈体的伤害。微流控细胞/组织/器官操作芯⽚是哺乳动物细胞以及微环境操作最重要的技术平台，渴望 应⽤于代替各类动物模型，模拟⼈体内环境(⼈体、组织芯⽚ [28] )，⽤于药物筛查递送，研究药物毒理和药 理作⽤，⼈体耐药性 [29] [30] . (b)基于激光打印技术制备 3D 纳⽶等离⼦体的示意图 [31] .…”