Three generations of thiolated cyclodextrins: A direct comparison of their mucus permeating and mucoadhesive properties

Soheil Haddadzadegan; Patrick Knoll; Richard Wibel; Gergely Kali; Andreas Bernkop-Schnürch

doi:10.1016/j.actbio.2023.05.050

Three generations of thiolated cyclodextrins: A direct comparison of their mucus permeating and mucoadhesive properties

Acta Biomater. 2023 Sep 1:167:309-320. doi: 10.1016/j.actbio.2023.05.050. Epub 2023 Jun 3.

Authors

Soheil Haddadzadegan¹, Patrick Knoll¹, Richard Wibel¹, Gergely Kali¹, Andreas Bernkop-Schnürch²

Affiliations

¹ Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria.
² Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria. Electronic address: andreas.bernkop@uibk.ac.at.

PMID: 37271247
DOI: 10.1016/j.actbio.2023.05.050

Abstract

Aim: This study aims to compare the mucus permeating and mucoadhesive properties of three generations of thiolated cyclodextrins (CDs).

Methods: Free thiol groups of thiolated γ-CDs (CD-SH) were S-protected with 2-mercaptonicotinic acid (MNA), leading to a second generation of thiolated CDs (CD-SS-MNA) and with 2 kDa polyethylene glycol (PEG) bearing a terminal thiol group leading to a third generation of thiolated CDs (CD-SS-PEG). The structure of these thiolated CDs was confirmed and characterized by FT-IR, ¹H NMR and colorimetric assays. Thiolated CDs were evaluated regarding viscosity, mucus diffusion, and mucoadhesion.

Results: The viscosity of the mixture of CD-SH, CD-SS-MNA, or CD-SS-PEG with mucus increased up to 11-, 16-, and 14.1-fold compared to unmodified CD within 3 hours, respectively. Mucus diffusion increased in the following rank order: unprotected CD-SH < CD-SS-MNA < CD-SS-PEG. The residence time of CD-SH, CD-SS-MNA, and CD-SS-PEG on porcine intestine was up to 9.6-, 12.55-, and 11.2-fold prolonged compared to native CD, respectively.

Conclusion: According to these results, S-protection of thiolated CDs can be a promising approach to improve their mucus permeating and mucoadhesive properties.

Statement of significance: Three generations of thiolated cyclodextrins (CDs) with different types of thiol ligands have been synthesized to improve mucus interaction. 1^st generation of thiolated CDs was synthesized by converting hydroxyl groups into thiols by reaction with Thiourea. For 2^nd generation, free thiol groups were S-protected by reaction with 2-mercaptonicotinic acid (MNA), resulting in high reactive disulfide bonds. For 3^rd generation, terminally thiolated short PEG chains (2 kDa) were used for S-protection of thiolated CDs. Mucus penetrating properties were found to be increased as follows: 1^st generation < 2^nd generation < 3^rd generation. Furthermore, mucoadhesive properties were improved in the following rank order: 1^st generation < 3^rd generation < 2^nd generation. This study suggests that the S-protection of thiolated CDs can enhance mucus penetrating and mucoadhesive properties.

Keywords: Drug delivery; Mucoadhesion; Mucosa; Rheological studies; S-protection; Saccharides; Thiolation.

MeSH terms

Animals
Caco-2 Cells
Cyclodextrins*
Drug Delivery Systems / methods
Humans
Mucus
Spectroscopy, Fourier Transform Infrared
Sulfhydryl Compounds / chemistry
Swine

Substances

2-mercaptonicotinic acid
Cyclodextrins
methoxypolyethylene glycol succinimidylsuccinate
Sulfhydryl Compounds