奥利司他是一种FDA认可的治疗肥胖症的脂肪酸抑制剂，具有某些低且差异极大的抗癌能力。在先前的研究中，我们揭示了奥利司他和多巴胺在癌症治疗中的协同作用。在这里，设计合成了具有定义化学结构的奥利司他-多巴胺结合物（ODC）。ODC按设计经历了氧化聚合和自组装，形成了纳米颗粒（纳米-ODC）。部分结晶结构的纳米-ODC显示出良好的水分散性，形成了稳定的纳米-ODC悬液。由于儿茶酚基团的生物粘附特性，一旦给药，纳米-ODC很快就会积累在细胞表面，并被癌细胞高效吞噬。在细胞质中，纳米-ODC经历了双相溶解，然后通过自发水解释放完整的奥利司他和多巴胺。除了细胞内反应性氧化物种（ROS）升高外，共定位的多巴胺还通过单胺氧化酶（MAOs）催化的多巴胺氧化诱导线粒体功能障碍。奥利司他和多巴胺之间的强烈协同作用确定了良好的细胞毒性活性和独特的细胞裂解机制，解释了纳米-ODC对耐药和敏感癌细胞的区别活性。这种新技术启用的奥利司他再利用将有助于克服药物耐药和改善癌症化疗。

Orlistat, an FDA-approved fatty acid inhibitor for obesity treatment, demonstrates certain low and greatly varied anticancer abilities. In a previous study, we revealed a synergistic effect between orlistat and dopamine in cancer treatment. Here, orlistat-dopamine conjugates (ODCs) with defined chemical structures were synthesized. The ODC by design underwent polymerization and self-assembly in the presence of oxygen to form nano-sized particles (Nano-ODCs) spontaneously. The resulted Nano-ODCs of partial crystalline structures demonstrated good water dispersion to form stable Nano-ODC suspensions. Because of the bioadhesive property of the catechol moieties, once administered, Nano-ODCs were quickly accumulated on cell surfaces and efficiently uptaken by cancer cells. In the cytoplasm, Nano-ODC experienced biphasic dissolution followed by spontaneous hydrolysis to release intact orlistat and dopamine. Besides elevated levels of intracellular reactive oxygen species (ROS), the co-localized dopamine also induced mitochondrial dysfunctions through monoamine oxidases (MAOs)-catalyzed dopamine oxidation. The strong synergistic effects between orlistat and dopamine determined a good cytotoxicity activity and a unique cell lysis mechanism, explaining the distinguished activity of Nano-ODC to drug-sensitive and -resistant cancer cells. This new technology-enabled orlistat repurposing will contribute to overcoming drug resistance and the improvement of cancer chemotherapy.