Thiolated α-cyclodextrin: The likely smallest drug carrier providing enhanced cellular uptake and endosomal escape

Özlem Kaplan; Martyna Truszkowska; Gergely Kali; Patrick Knoll; Mariana Blanco Massani; Doris Elfriede Braun; Andreas Bernkop-Schnürch

doi:10.1016/j.carbpol.2023.121070

Thiolated α-cyclodextrin: The likely smallest drug carrier providing enhanced cellular uptake and endosomal escape

Carbohydr Polym. 2023 Sep 15:316:121070. doi: 10.1016/j.carbpol.2023.121070. Epub 2023 May 31.

Authors

Özlem Kaplan¹, Martyna Truszkowska², Gergely Kali², Patrick Knoll², Mariana Blanco Massani², Doris Elfriede Braun², Andreas Bernkop-Schnürch³

Affiliations

¹ Department of Genetics and Bioengineering, Rafet Kayış Faculty of Engineering, Alanya Alaaddin Keykubat University, 07400 Antalya, Turkey; Department of Molecular Biology and Genetics, Faculty of Science, Istanbul University, 34134 Istanbul, Turkey.
² Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria.
³ Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80-82, A-6020 Innsbruck, Austria. Electronic address: [email protected].

PMID: 37321712
DOI: 10.1016/j.carbpol.2023.121070

Abstract

This study aimed to evaluate the effect of thiolated α-cyclodextrin (α-CD-SH) on the cellular uptake of its payload. For this purpose, α-CD was thiolated using phosphorous pentasulfide. Thiolated α-CD was characterized by FT-IR and ¹H NMR spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffractometry (PXRD). Cytotoxicity of α-CD-SH was evaluated on Caco-2, HEK 293, and MC3T3 cells. Dilauryl fluorescein (DLF) and coumarin-6 (Cou) serving as surrogates for a pharmaceutical payload were incorporated in α-CD-SH, and cellular uptake was analyzed by flow cytometry and confocal microscopy. Endosomal escape was investigated by confocal microscopy and hemolysis assay. Results showed no cytotoxic effect within 3 h, while dose-dependent cytotoxicity was observed within 24 h. The cellular uptake of DLF and Cou was up to 20- and 11-fold enhanced by α-CD-SH compared to native α-CD, respectively. Furthermore, α-CD-SH provided an endosomal escape. According to these results, α-CD-SH is a promising carrier to shuttle drugs into the cytoplasm of target cells.

Keywords: Cellular uptake; Cyclodextrin; Endosomal escape; Thiol-mediated cellular uptake; Thiolated cyclodextrin.

MeSH terms

Caco-2 Cells
Calorimetry, Differential Scanning
Drug Carriers* / chemistry
Drug Carriers* / toxicity
HEK293 Cells
Humans
Solubility
Spectroscopy, Fourier Transform Infrared
X-Ray Diffraction
alpha-Cyclodextrins* / chemistry
alpha-Cyclodextrins* / pharmacology

Substances

Drug Carriers
alpha-Cyclodextrins