The effects of native and modified CDs in human renal proximal tubule cells was studied using complementary imaging, flow cytometry, and MALDI-TOF mass spectrometry. Distinct, host-dependent responses were observed. α-Cyclodextrin induced rapid membrane disruption at elevated concentrations, whereas methylated β-cyclodextrin (Meβ-CD) produced a progressive phenotype characterized by increased membrane permeability, impaired lipid internalization, and reduced cell proliferation under sub-lethal conditions. Despite these differences, both Meβ-CD and γ-cyclodextrin enhanced cholesterol internalization without evidence of immediate depletion, indicating modulation of endogenous transport processes. In contrast, Meβ-CD selectively disrupted membrane lipid uptake and altered extracellular lipid composition, yielding vesicle fractions enriched in cholesterol esters and ceramides but depleted in phosphoinositides. These findings support a model in which cyclodextrins perturb phosphoinositide-dependent lipid trafficking pathways, providing a mechanistic link between altered lipid distribution and cytotoxic response, and informing the design of safer CD-based therapeutics.
- Cyclodextrins induce structure-dependent cytotoxicity in renal epithelial cells
- Acute exposure to high concentrations of α-CD causes rapid membrane disruption, while Meβ-CD induces membrane permeabilization.
- Both Meβ- and γ-CD enhance cholesterol redistribution without observed depletion. internalization, Meβ-CD selectively and progressively impairs membrane lipid indicating disruption of lipid trafficking, potentially hindering cell proliferation and growth.
- Both Meβ- and γ-CD alter lipid sorting, yielding phosphoinositides-depleted, cholesterol- and ceramide-rich extracellular vesicles
Daniel Da Costa Pereira, David A. Poole. Disruption of Lipid Sorting and Endosomal Transport in Cyclodextrin-mediated Cytotoxicity. ChemRxiv. 21 July 2026.
DOI: https://doi.org/10.26434/chemrxiv.15006417/v1
Featured image: Szente, L., Cholesterolcomplex with beta- (a) and g-cyclodextrin (b) (Fenyvesi, É. Cyclodextrin-Lipid Complexes: Cavity Size Matters. Struct Chem 28, 479–492 (2017). https://doi.org/10.1007/s11224-016-0884-9)