通过非环状库克尔[n]烯自组装形成的响应性超分子纳米胶囊，用于靶向癌细胞的药物递送

基于宿主-客体识别、非共价相互作用的超分子药物递送系统（SDDS），具有响应性行为和对外部刺激的动态调控能力，在癌症治疗中引起广泛关注。本研究设计并合成了一种靶向双功能药物递送系统。一个亲水性大环宿主分子（非环状库克尔[n]烯 ACB）被修饰有叶酸（FA）作为靶向配体。客体分子由连接有二硫键的猿桃烷（DA）和大麻二酚（CBD）组成，响应元素为谷胱甘肽（GSH）相关结构。宿主与客体分子的识别与自组装成功形成超分子纳米胶囊（SNMs），实现靶向癌细胞并在高谷胱甘肽环境中释放药物。利用核磁共振（NMR）、荧光滴定、傅里叶变换红外光谱（FT-IR）和热分析（TGA）研究了宿主-客体的相互作用。透射电子显微镜（TEM）和动态光散射（DLS）确认了SNMs的纳米结构。与二硝基苯甲酸（DTNB）反应的实验表明SNMs对GSH具有响应性。体外细胞毒性试验显示，SNMs对四种癌细胞（HeLa、HCT-116、A549和HepG2）的靶向效率优于正常细胞293T。细胞摄取研究显示HeLa细胞更易摄取SNMs，导致其在肿瘤细胞质中积累。荧光共定位实验验证SNMs能有效积聚于线粒体和内质网等能量代谢与信号通路相关的细胞器，影响细胞的代谢性死亡。流式细胞术和共聚焦核染色试验均确认SNMs能有效诱导凋亡，最终导致癌细胞死亡。这些结果表明SNMs具有优异的靶向性、响应性、高生物利用度和稳定性，具有巨大潜力在药物递送领域应用。

The supramolecular drug delivery systems (SDDSs) based on host-guest recognition through noncovalent interactions, capable of responsive behavior and dynamic switching to external stimuli, have attracted considerable attention in cancer therapy. In this study, a targeted dual-functional drug delivery system was designed and synthesized. A hydrophilic macrocyclic host molecule (acyclic cucurbit[n]uril ACB) was modified with folic acid (FA) as a targeting ligand. The guest molecule consists of a disulfide bond attached to adamantane (DA) and cannabidiol (CBD) at both ends of the response element of glutathione. Recognition and self-assembly of host and guest molecules successfully functionalize supramolecular nanomicelles (SNMs), targeting cancer cells and releasing drugs in a high glutathione environment. The interactions between host and guest molecules were investigated by using nuclear magnetic resonance (NMR), fluorescence titration, Fourier-transform infrared spectroscopy (FT-IR), and thermal analysis (TGA). Transmission electron microscopy (TEM) and dynamic light scattering (DLS) confirmed the nanostructure of the SNMs. Experimentation with 5,5'-dithiobis (2-nitrobenzoic acid) (DTNB) demonstrated the responsiveness of SNMs to glutathione (GSH). In vitro cytotoxicity assays demonstrated that SNMs had a greater targeting efficacy for four types of cancer cells (HeLa, HCT-116, A549, and HepG2) compared to normal 293T cells. Cellular uptake studies revealed that HeLa cells more readily absorbed SNMs, leading to their accumulation in the tumor cell cytoplasm. Fluorescence colocalization assays verified that SNMs efficiently accumulated in organelles related to energy metabolism and signaling, including mitochondria and the endoplasmic reticulum, affecting cellular metabolic death. Both flow cytometry and confocal nuclear staining assays confirmed that SNMs effectively induced apoptosis over time, ultimately resulting in the death of cancer cells. These findings demonstrate that SNMs exhibit excellent targeting ability, responsiveness, high bioavailability, and stability, suggesting significant potential in drug delivery applications.