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While the bioavailability and biological behaviour of native cyclodextrins have been extensively investigated, considerably less information is available regarding modified cyclodextrin polymers. Therefore, the present study aimed to investigate the permeation and cellular uptake of an epichlorohydrin-crosslinked \u03b2-cyclodextrin polymer using multiple in vitro and ex vivo models. Methods: Fluorescently labelled \u03b2-cyclodextrin polymers were applied in all experiments. Membrane permeation studies were performed using an in-line diffusion cell system with membranes of different pore sizes. In vitro transport and cellular uptake were investigated on HaCaT, Caco-2, and TR146 cell monolayers, while ex vivo permeation studies were carried out using skin, buccal, and intestinal tissues. Results: The results demonstrated a strong size-dependent transport behaviour across synthetic membranes. Cell monolayer studies revealed cell-line-dependent differences in polymer intracellular distribution. Lysosomal accumulation was observed in HaCaT and Caco-2 cells, whereas no intracellular accumulation was detected in TR146 cells. These findings suggest differences in polymer permeation among the investigated cell models. Ex vivo studies demonstrated the tissue permeation of cyclodextrin polymers, with marked accumulation within skin layers, indicating predominant dermal retention. Furthermore, strong correlations were identified between the in vitro and ex vivo skin and intestinal models. Conclusions: Overall, the findings demonstrate that \u03b2-cyclodextrin polymers exhibit complex, barrier-dependent transport behaviour across different biological models. The observed differences in permeation and intracellular localization suggest that multiple transport processes may contribute to their biological interactions, which provide a foundation for future studies aimed at elucidating the molecular mechanisms governing polymer uptake and permeation.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070854","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T03:06:52Z","timestamp":1784084812000},"page":"854","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Vitro and Ex Vivo Studies on the Absorption and Distribution of \u03b2-Cyclodextrin Polymer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6686-3771","authenticated-orcid":false,"given":"R\u00e9ka","family":"R\u00e9v\u00e9sz","sequence":"first","affiliation":[{"name":"Doctoral School of Pharmaceutical Sciences, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary"},{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Rex Ferenc Street 1, H-4002 Debrecen, Hungary"},{"name":"Department of Industrial Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Rex Ferenc Street 1, H-4002 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akay Dogan","family":"Mengenli","sequence":"additional","affiliation":[{"name":"Doctoral School of Pharmaceutical Sciences, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary"},{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Rex Ferenc Street 1, H-4002 Debrecen, Hungary"},{"name":"Department of Industrial Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Rex Ferenc Street 1, H-4002 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8837-7499","authenticated-orcid":false,"given":"\u00c1gnes","family":"Ruszny\u00e1k","sequence":"additional","affiliation":[{"name":"Department of Molecular and Nanopharmaceutics, Faculty of Pharmacy, University of Debrecen, Rex Ferenc Street 1, H-4002 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1640-3295","authenticated-orcid":false,"given":"Rich\u00e1rd","family":"Kajt\u00e1r","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, University of Debrecen, Rex Ferenc Street 1, H-4002 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0992-4176","authenticated-orcid":false,"given":"Istv\u00e1n","family":"Lekli","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, University of Debrecen, Rex Ferenc Street 1, H-4002 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8663-2890","authenticated-orcid":false,"given":"Ildik\u00f3","family":"B\u00e1cskay","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Rex Ferenc Street 1, H-4002 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2123-5821","authenticated-orcid":false,"given":"\u00c1d\u00e1m","family":"Haimhoffer","sequence":"additional","affiliation":[{"name":"Doctoral School of Pharmaceutical Sciences, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary"},{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Rex Ferenc Street 1, H-4002 Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1021\/cr970022c","article-title":"Introduction and general overview of cyclodextrin chemistry","volume":"98","author":"Szejtli","year":"1998","journal-title":"Chem. 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