While β-cyclodextrins are commonly associated with cholesterol extraction, it remains unclear whether this mechanism alone explains their biological activity. Here, we investigate the effects of native and modified CDs in human renal proximal tubule cells using complementary imaging, flow cytometry, and MALDI mass spectrometry. Distinct, host-dependent responses were observed.
- α-CD causes rapid membrane disruption above a sharp concentration threshold, with no sub-lethal effects below it.
- Both Meβ- and γ-CD enhance cholesterol redistribution without observed depletion or accompanying toxicity.
- Meβ-CD arrests membrane lipid internalization at sub-lethal concentrations and suppresses proliferation under chronic exposure.
- The proliferative deficit occurs with native β-CD but not with HPβ-CD, implicating rim substitution..
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
Daniel Da Costa Pereira, David A. Poole (2026) Disruption of endosomal transport in cyclodextrin-mediated cytotoxicity. Biomedicine & Pharmacotherapy 204, 119973. https://doi.org/10.1016/j.biopha.2026.119973.