Chlorambucil (Cbl) is a DNA alkylating drug in the nitrogen mustard family, but the clinical applications of nitrogen mustard antitumor drugs are frequently limited by their poor aqueous solubility, poor cellular uptake, lack of targeting, and severe side effects. Additionally, mitochondria are the energy factories for cells, and tumor cells are more susceptible to mitochondrial dysfunction than some healthy cells, thus making mitochondria an important target for tumor therapy. As a proof-of-concept, direct delivery of Cbl to tumor cells’ mitochondria will probably bring about new opportunities for the nitrogen mustard family. Furthermore, IR775 chloride is a small-molecule lipophilic cationic heptamethine cyanine dye with potential advantages of mitochondria targeting, near-infrared (NIR) fluorescence imaging, and preferential internalization towards tumor cells. Here, an amphiphilic drug conjugate was facilely prepared by covalently coupling chlorambucil with IR775 chloride and further self-assembly to form a carrier-free self-delivery theranostic system, in which the two components are both functional units aimed at theranostic improvement. The theranostic IR775-Cbl potentiated typical “1 + 1 > 2” tumor inhibition through specific accumulation in mitochondria, which triggered a remarkable decrease in mitochondrial membrane potential and ATP generation. In vivo biodistribution and kinetic monitoring were achieved by real-time NIR fluorescence imaging to observe its transport inside a living body. Current facile mitochondria-targeting modification with clinically applied drugs was promising for endowing traditional drugs with targeting, imaging, and improved potency in disease theranostics.

中文翻译：

---

线粒体靶向七次甲基花青-苯丁酸氮芥配制的聚合物纳米颗粒可增强天然肿瘤化疗功效

苯丁酸氮芥（Cbl）是氮芥家族中的一种DNA烷基化药物，但氮芥抗肿瘤药物的临床应用往往因其水溶性差、细胞摄取差、缺乏靶向性和严重的副作用而受到限制。此外，线粒体是细胞的能量工厂，肿瘤细胞比一些健康细胞更容易受到线粒体功能障碍的影响，因此线粒体成为肿瘤治疗的重要靶点。作为概念验证，将 Cbl 直接递送至肿瘤细胞的线粒体可能会给氮芥家族带来新的机会。此外，IR775氯化物是一种小分子亲脂性阳离子七次甲基花青染料，具有线粒体靶向、近红外（NIR）荧光成像和对肿瘤细胞优先内化的潜在优势。在这里，通过将苯丁酸氮芥与IR775氯化物共价偶联并进一步自组装以形成无载体的自递送治疗诊断系统，轻松制备了两亲性药物缀合物，其中两个组件都是旨在改善治疗诊断的功能单元。治疗诊断 IR775-Cbl 通过在线粒体中的特异性积累来增强典型的“1 + 1 > 2”肿瘤抑制作用，从而引发线粒体膜电位和 ATP 生成的显着降低。通过实时近红外荧光成像实现体内生物分布和动力学监测，观察其在活体内的运输。目前临床应用药物对线粒体靶向的简便修饰有望赋予传统药物靶向、成像和提高疾病治疗诊断的效力。