Responsive Supramolecular Nanomicelles Formed through\nSelf-Assembly of Acyclic Cucurbit[<i>n</i>]uril for Targeted\nDrug Delivery to Cancer Cells

The\nsupramolecular drug delivery systems (SDDSs) based on host–guest\nrecognition through noncovalent interactions, capable of responsive\nbehavior and dynamic switching to external stimuli, have attracted\nconsiderable attention in cancer therapy. In this study, a targeted\ndual-functional drug delivery system was designed and synthesized.\nA hydrophilic macrocyclic host molecule (acyclic cucurbit[<i>n</i>]uril ACB) was modified with folic acid (FA) as a targeting\nligand. The guest molecule consists of a disulfide bond attached to\nadamantane (DA) and cannabidiol (CBD) at both ends of the response\nelement of glutathione. Recognition and self-assembly of host and\nguest molecules successfully functionalize supramolecular nanomicelles\n(SNMs), targeting cancer cells and releasing drugs in a high glutathione\nenvironment. The interactions between host and guest molecules were\ninvestigated by using nuclear magnetic resonance (NMR), fluorescence\ntitration, Fourier-transform infrared spectroscopy (FT-IR), and thermal\nanalysis (TGA). Transmission electron microscopy (TEM) and dynamic\nlight scattering (DLS) confirmed the nanostructure of the SNMs. Experimentation\nwith 5,5′-dithiobis (2-nitrobenzoic acid) (DTNB) demonstrated\nthe responsiveness of SNMs to glutathione (GSH). In vitro cytotoxicity\nassays demonstrated that SNMs had a greater targeting efficacy for\nfour types of cancer cells (HeLa, HCT-116, A549, and HepG2) compared\nto normal 293T cells. Cellular uptake studies revealed that HeLa cells\nmore readily absorbed SNMs, leading to their accumulation in the tumor\ncell cytoplasm. Fluorescence colocalization assays verified that SNMs\nefficiently accumulated in organelles related to energy metabolism\nand signaling, including mitochondria and the endoplasmic reticulum,\naffecting cellular metabolic death. Both flow cytometry and confocal\nnuclear staining assays confirmed that SNMs effectively induced apoptosis\nover time, ultimately resulting in the death of cancer cells. These\nfindings demonstrate that SNMs exhibit excellent targeting ability,\nresponsiveness, high bioavailability, and stability, suggesting significant\npotential in drug delivery applications.