{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:01:20Z","timestamp":1787029280149,"version":"build-2736575974"},"reference-count":48,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Polysorbate 80 (PS80), a complex surfactant mixture, is widely recognized for its ability to enhance drug permeation across the blood\u2013brain barrier (BBB). While this effect is generally attributed to the combined actions of its components, the specific contribution and potential selectivity of individual minor components remain poorly understood. This study therefore aimed to isolate and compare the primary minor components of PS80 to determine whether they uniformly enhance BBB permeation or exhibit drug-specific functions. Methods: In this research, four primary minor components of PS80\u2014polyoxyethylene sorbitan monooleate (PSM), polyoxyethylene isosorbide monooleate (PIM), polyoxyethylene sorbitan dioleate (PSD), and a polyethylene glycol\/polyoxyethylene sorbitan\/polyoxyethylene isosorbide mixture (PEG\/PS\/PI mixture)\u2014were isolated using preparative liquid-phase chromatography. Drug-loaded formulations were then prepared using the solvent evaporation method incorporating five model drugs: 1,1\u2032-dioctadecyl-3,3,3\u2032,3\u2032-tetramethylindotricarbocyanine iodide (DiR, MW = 1013.39 Da), donepezil (MW = 379.49 Da), nimodipine (MW = 418.44 Da), chlorogenic acid (MW = 354.31 Da), and paclitaxel (MW = 853.92 Da). The permeability of these formulations across the BBB was evaluated in BALB\/c mice after intravenous administration. Brain distribution of the lipophilic dye DiR was assessed using fluorescence imaging, whereas brain homogenate concentrations of therapeutic drugs were quantified by UPLC-MS\/MS. Results: Results revealed that the enhancement of brain delivery was dependent on both the specific minor component and the drug. The PEG\/PS\/PI mixture specially enhanced the brain homogenate concentration of donepezil to 11.8 \u00b1 1.2 ng\/mL, representing a 6.9-fold enhancement, while PIM micelles increased the delivery of DiR, donepezil, and nimodipine. In contrast, PSM and PSD micelles improved transport of only DiR and donepezil. The broad performance of PIM suggests a more flexible formulation\u2014a hypothesis that warrants further validation. Conversely, none of the different minor components enhanced the delivery of chlorogenic acid or paclitaxel, underscoring the critical role of specific drug\u2013component interactions. Conclusions: This component-resolved insight challenges the conventional perception of PS80 and provides a rational framework for engineering precision brain-targeted delivery systems by selecting functional minor components.<\/jats:p>","DOI":"10.3390\/pharmaceutics17121572","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T15:11:24Z","timestamp":1764947484000},"page":"1572","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Drug-Dependent Enhancement of Blood\u2013Brain Barrier Permeation by Polysorbate 80 Minor Components"],"prefix":"10.3390","volume":"17","author":[{"given":"Xiaofeng","family":"Wang","sequence":"first","affiliation":[{"name":"National Institutes for Food and Drug Control, 2 Tiantan Xili, Dongcheng District, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue","family":"Wang","sequence":"additional","affiliation":[{"name":"National Institutes for Food and Drug Control, 2 Tiantan Xili, Dongcheng District, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Zhao","sequence":"additional","affiliation":[{"name":"National Institutes for Food and Drug Control, 2 Tiantan Xili, Dongcheng District, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Langui","family":"Xie","sequence":"additional","affiliation":[{"name":"National Institutes for Food and Drug Control, 2 Tiantan Xili, Dongcheng District, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3046-5688","authenticated-orcid":false,"given":"Rui","family":"Yang","sequence":"additional","affiliation":[{"name":"National Institutes for Food and Drug Control, 2 Tiantan Xili, Dongcheng District, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunmeng","family":"Sun","sequence":"additional","affiliation":[{"name":"Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiasheng","family":"Tu","sequence":"additional","affiliation":[{"name":"Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Sun","sequence":"additional","affiliation":[{"name":"National Institutes for Food and Drug Control, 2 Tiantan Xili, Dongcheng District, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1038\/jcbfm.2015.76","article-title":"Cerebrospinal Fluid Biomarkers of Neurovascular Dysfunction in Mild Dementia and Alzheimer\u2019S Disease","volume":"35","author":"Sweeney","year":"2015","journal-title":"J. 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