Trigonometric Bundling Disulfide Unit Starship Synergizes More Effectively to Promote Cellular Uptake

A small molecule disulfide unit technology platform based on dynamic thiol exchange chemistry at the cell membrane has the potential for drug delivery. However, the alteration of the CSSC dihedral angle of the disulfide unit caused by diverse substituents directly affects the effectiveness of this t...

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Bibliographic Details
Published in:International journal of molecular sciences 2024-07, Vol.25 (14), p.7518
Main Authors: Wang, Lei, Wang, Dezhi, Lei, Wenzhuo, Sun, Tiantian, Gu, Bei, Dong, Han, Taniguchi, Yosuke, Liu, Yichang, Ling, Yong
Format: Article
Language:English
Subjects:
Cells
cellular uptake
Cytoplasm
cytosolic delivery
Cytotoxicity
disulfide unit
Drug delivery systems
Drugs
Efficiency
Membrane lipids
Molecular dynamics
Peptides
Polymerization
Thiols
Vehicles
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Summary:A small molecule disulfide unit technology platform based on dynamic thiol exchange chemistry at the cell membrane has the potential for drug delivery. However, the alteration of the CSSC dihedral angle of the disulfide unit caused by diverse substituents directly affects the effectiveness of this technology platform as well as its own chemical stability. The highly stable open-loop relaxed type disulfide unit plays a limited role in drug delivery due to its low dihedral angle. Here, we have built a novel disulfide unit starship based on the 3,4,5-trihydroxyphenyl skeleton through trigonometric bundling. The intracellular delivery results showed that the trigonometric bundling of the disulfide unit starship effectively promoted cellular uptake without any toxicity, which is far more than 100 times more active than that of equipment with a single disulfide unit in particular. Then, the significant reduction in cell uptake capacity (73-93%) using thiol erasers proves that the trigonometric bundling of the disulfide starship is an endocytosis-independent internalization mechanism via a dynamic covalent disulfide exchange mediated by thiols on the cell surface. Furthermore, analysis of the molecular dynamics simulations demonstrated that trigonometric bundling of the disulfide starship can significantly change the membrane curvature while pushing lipid molecules in multiple directions, resulting in a significant distortion in the membrane structure and excellent membrane permeation performance. In conclusion, the starship system we built fully compensates for the inefficiency deficiencies induced by poor dihedral angles.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms25147518