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Dithiolane quartets: thiol-mediated uptake enables cytosolic delivery in deep tissue
Rémi Martinent1, Salman Tawffik1, Javier López-Andarias1
1Department of Organic Chemistry, University of Geneva Geneva Switzerland stefan.matile@unige.ch https://www.unige.ch/sciences/chiorg/matile/ +41 22 379 6523.
Chemical Science
|November 11, 2021
Summary
Thiol-mediated uptake enables efficient cytosolic delivery into 3D multicellular spheroids and deep tissues, overcoming limitations of traditional methods. This breakthrough utilizes supramolecular chemistry principles for targeted delivery and controlled release.
Area of Science:
- Biotechnology
- Supramolecular Chemistry
- Cellular Delivery Systems
Background:
- Traditional drug delivery systems struggle with efficient penetration into deep tissues and 3D multicellular spheroids.
- Polycationic cell-penetrating peptides exhibit limited efficacy in complex biological environments.
- Targeted cytosolic delivery remains a significant challenge in advanced therapeutic strategies.
Purpose of the Study:
- To report a novel thiol-mediated uptake mechanism for efficient substrate delivery into 3D spheroids and deep tissues.
- To investigate the supramolecular chemistry principles governing transcytosis and cytosolic delivery.
- To demonstrate the utility of this method for targeted delivery of quantum dots and controlled release of mechanophores.
Main Methods:
- Development and application of thiol-mediated uptake strategies for substrate delivery.
- Translation of the 2D chloroalkane penetration assay (CAPA) to 3D deep tissue models for quantitative cytosolic detection.
- Introduction of dithiolane quartets on streptavidin templates as modular transporters.
Main Results:
- Successful cytosolic delivery of various substrates into 3D multicellular spheroids via thiol-mediated uptake.
- Demonstration of pH-dependent disulfide exchange principles for deep tissue transcytosis.
- Targeted delivery of quantum dots and controlled release of mechanophores exemplified the system's efficacy.
Conclusions:
- Thiol-mediated uptake offers a significant advantage for general cytosolic delivery into deep tissues.
- Modular dithiolane quartets on streptavidin templates provide versatile and efficient transport motifs.
- This approach expands streptavidin biotechnology and enhances the utility of supramolecular chemistry in drug delivery.
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