Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, PR China.
Mol Pharm. 2024 Nov 4;21(11):5784-5796. doi: 10.1021/acs.molpharmaceut.4c00796. Epub 2024 Oct 7.
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[]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.
基于主客体识别的超分子药物递送系统（SDDS）通过非共价相互作用，能够对外部刺激做出响应行为和动态切换，在癌症治疗中引起了相当大的关注。在这项研究中，设计并合成了一种靶向的双重功能药物递送系统。亲水性大环主体分子（无环葫芦[ ]脲 ACB）被修饰为叶酸（FA）作为靶向配体。客体分子由连接到金刚烷（DA）和大麻二酚（CBD）的二硫键组成，位于谷胱甘肽的响应元件的两端。主体和客体分子的识别和自组装成功地功能化了超分子纳米胶束（SNMs），靶向癌细胞并在高谷胱甘肽环境中释放药物。通过使用核磁共振（NMR）、荧光滴定、傅里叶变换红外光谱（FT-IR）和热分析（TGA）研究了主体和客体分子之间的相互作用。透射电子显微镜（TEM）和动态光散射（DLS）证实了 SNMs 的纳米结构。使用 5,5'-二硫代双（2-硝基苯甲酸）（DTNB）的实验表明，SNMs 对谷胱甘肽（GSH）具有响应性。体外细胞毒性实验表明，与正常 293T 细胞相比，SNMs 对四种癌细胞（HeLa、HCT-116、A549 和 HepG2）具有更大的靶向功效。细胞摄取研究表明，HeLa 细胞更容易吸收 SNMs，导致其在肿瘤细胞质中积累。荧光共定位实验证实，SNMs 能够有效地在与能量代谢和信号转导相关的细胞器中积累，包括线粒体和内质网，影响细胞代谢性死亡。流式细胞术和共聚焦核染色实验均证实，SNMs 能够随着时间的推移有效诱导细胞凋亡，最终导致癌细胞死亡。这些发现表明，SNMs 表现出优异的靶向能力、响应性、高生物利用度和稳定性，在药物递送应用中具有重要的潜在价值。
