{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:13:54Z","timestamp":1788322434750,"version":"build-2803163510"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T00:00:00Z","timestamp":1765843200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T00:00:00Z","timestamp":1765843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"NIH\/NCI","award":["R01 CA231210-01A1"],"award-info":[{"award-number":["R01 CA231210-01A1"]}]},{"DOI":"10.13039\/100017932","name":"Western University of Health Sciences","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100017932","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pharm Res"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Lung cancer chemoprevention modalities are gaining wide attention as it is the second most diagnosed cancer type and the leading cause of cancer-related deaths. Our previous studies reported unique lung cancer chemoprevention capability with a repurposed drug combination of sulfasalazine (SAS) and disulfiram (DSF). However, their efficacy is limited by poor bioavailability. To overcome this challenge, we developed bioenhanced oil-in-water (o\/w) nano self-emulsifying drug delivery system (Nano-SEDDS) formulations of SAS and DSF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Unique isotropic Nano-SEDDS of SAS and DSF were developed and optimized using a single-step mix method followed by\n                      <jats:italic>in vitro<\/jats:italic>\n                      physicochemical characterization and stability studies\n                      <jats:italic>.<\/jats:italic>\n                      An\n                      <jats:italic>in vivo<\/jats:italic>\n                      pharmacokinetic and tissue-biodistribution study was undertaken to test the proposed hypothesis of bioavailability enhancement with Nano-SEDDS of SAS and DSF.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The optimal Nano-SEDDS formulation exhibited low nanodroplet sizes (&lt;\u2009200\u00a0nm), high drug content, and 4.5-fold (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) and 3.75-fold (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) enhancement in\n                      <jats:italic>in vitro<\/jats:italic>\n                      dissolution of SAS and DSF compared to the respective free drugs. The Nano-SEDDS formulations were also confirmed to be stable at room temperature in compliance with ICH guidelines. Further, SAS Nano-SEDDS showed a dose-dependent increment in oral bioavailability as shown by a significant 7.9-fold (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001) enhancement in dose-normalized AUC at a dose of 10\u00a0mg\/kg compared to free drug treatment at a control dose of 250\u00a0mg\/kg.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Overall, the studies corroborated the successful formulation of bioavailability-enhanced SAS and DSF Nano-SEDDS with future co-delivery applications for lung cancer prevention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s11095-025-03964-7","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T17:23:26Z","timestamp":1765905806000},"page":"195-215","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Development, Optimization, and Evaluation of Nano Self-Emulsifying Drug Delivery System Formulation Platform for Oral Bioavailability Enhancement of Sulfasalazine and Disulfiram in Lung Cancer Chemoprevention"],"prefix":"10.1007","volume":"43","author":[{"given":"Preshita","family":"Desai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Bang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed Riaz Hasan","family":"Chowdhury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijun Kevin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunil","family":"Prabhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueqing","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fekadu","family":"Kassie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,16]]},"reference":[{"key":"3964_CR1","unstructured":"AmericanCancerSociety. Key Statistics for Lung Cancer 2025 [Available from: https:\/\/www.cancer.org\/cancer\/types\/lung-cancer\/about\/key-statistics.html. Accessed 25 Mar 2025."},{"issue":"1","key":"3964_CR2","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/s41392-025-02167-1","volume":"10","author":"J Ren","year":"2025","unstructured":"Ren J, Yan G, Yang L, Kong L, Guan Y, Sun H, et al. Cancer chemoprevention: signaling pathways and strategic approaches. Signal Transduct Target Ther. 2025;10(1):113.","journal-title":"Signal Transduct Target Ther"},{"key":"3964_CR3","doi-asserted-by":"crossref","unstructured":"Meyskens FL, Jr., Mukhtar H, Rock CL, Cuzick J, Kensler TW, Yang CS, et al. Cancer Prevention: Obstacles, Challenges and the Road Ahead. J Natl Cancer Inst. 2016;108(2):djv309.","DOI":"10.1093\/jnci\/djv309"},{"issue":"4","key":"3964_CR4","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1093\/carcin\/bgad020","volume":"44","author":"AJ Bagherpoor","year":"2023","unstructured":"Bagherpoor AJ, Shameem M, Luo X, Seelig D, Kassie F. Inhibition of lung adenocarcinoma by combinations of sulfasalazine (SAS) and disulfiram-copper (DSF-Cu) in cell line models and mice. Carcinogenesis. 2023;44(4):291\u2013303.","journal-title":"Carcinogenesis"},{"key":"3964_CR5","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.jiec.2021.10.028","volume":"106","author":"M Agafonov","year":"2022","unstructured":"Agafonov M, Garibyan A, Terekhova I. Improving pharmacologically relevant properties of sulfasalazine loaded in \u03b3-cyclodextrin-based metal organic framework. J Ind Eng Chem. 2022;106:189\u201397.","journal-title":"J Ind Eng Chem"},{"issue":"2","key":"3964_CR6","doi-asserted-by":"publisher","first-page":"320","DOI":"10.2174\/0122117385269522231113041029","volume":"13","author":"M Mathew","year":"2025","unstructured":"Mathew M, Patil A, G H. Development and characterization of Sulfasalazine cubosomes for potential transdermal drug delivery. Pharm Nanotechnol. 2025;13(2):320\u20137.","journal-title":"Pharm Nanotechnol"},{"issue":"1","key":"3964_CR7","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.ijpharm.2015.11.029","volume":"497","author":"M Shergill","year":"2016","unstructured":"Shergill M, Patel M, Khan S, Bashir A, McConville C. Development and characterisation of sustained release solid dispersion oral tablets containing the poorly water soluble drug disulfiram. Int J Pharm. 2016;497(1):3\u201311.","journal-title":"Int J Pharm"},{"key":"3964_CR8","doi-asserted-by":"publisher","first-page":"105590","DOI":"10.1016\/j.ejps.2020.105590","volume":"156","author":"Y Qu","year":"2021","unstructured":"Qu Y, Sun X, Ma L, Li C, Xu Z, Ma W, et al. Therapeutic effect of disulfiram inclusion complex embedded in hydroxypropyl-\u03b2-cyclodextrin on intracranial glioma-bearing male rats via intranasal route. Eur J Pharm Sci. 2021;156:105590.","journal-title":"Eur J Pharm Sci"},{"key":"3964_CR9","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics12030524","author":"J Lanz","year":"2023","unstructured":"Lanz J, Biniaz-Harris N, Kuvaldina M, Jain S, Lewis K, Fallon BA. Disulfiram: mechanisms, applications, and challenges. Antibiotics. 2023. https:\/\/doi.org\/10.3390\/antibiotics12030524.","journal-title":"Antibiotics"},{"issue":"2","key":"3964_CR10","doi-asserted-by":"publisher","first-page":"e87","DOI":"10.1016\/j.ddtec.2011.12.001","volume":"9","author":"PP Desai","year":"2012","unstructured":"Desai PP, Date AA, Patravale VB. Overcoming poor oral bioavailability using nanoparticle formulations \u2013 opportunities and limitations. Drug Discov Today Technol. 2012;9(2):e87\u201395.","journal-title":"Drug Discov Today Technol"},{"issue":"3","key":"3964_CR11","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1007\/s13346-019-00619-0","volume":"9","author":"P Desai","year":"2019","unstructured":"Desai P, Thakkar A, Ann D, Wang J, Prabhu S. Loratadine self-microemulsifying drug delivery systems (SMEDDS) in combination with sulforaphane for the synergistic chemoprevention of pancreatic cancer. Drug Deliv Transl Res. 2019;9(3):641\u201351.","journal-title":"Drug Deliv Transl Res"},{"issue":"2","key":"3964_CR12","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/s11095-019-2737-x","volume":"37","author":"P Desai","year":"2020","unstructured":"Desai P, Wang KZ, Ann D, Wang J, Prabhu S. Efficacy and pharmacokinetic considerations of Loratadine nanoformulations and its combinations for pancreatic cancer chemoprevention. Pharm Res. 2020;37(2):21.","journal-title":"Pharm Res"},{"issue":"4","key":"3964_CR13","first-page":"354","volume":"6","author":"MB Chaudhari","year":"2016","unstructured":"Chaudhari MB, Desai PP, Patel PA, Patravale VB. Solid lipid nanoparticles of amphotericin B (AmbiOnp): in vitro and in vivo assessment towards safe and effective oral treatment module. Drug Deliv Transl Res. 2016;6(4):354\u201364.","journal-title":"Drug Deliv Transl Res"},{"key":"3964_CR14","doi-asserted-by":"publisher","first-page":"114394","DOI":"10.1016\/j.colsurfb.2024.114394","volume":"246","author":"X Yan","year":"2025","unstructured":"Yan X, Li Q, Xiao S, Chen J, Song W. Sulfasalazine-loaded nanoframes: a new frontier in bladder cancer therapy through ferroptosis induction. Colloids Surf B Biointerfaces. 2025;246:114394.","journal-title":"Colloids Surf B Biointerfaces"},{"key":"3964_CR15","first-page":"100307","volume":"8","author":"D Huang","year":"2024","unstructured":"Huang D, Yao Y, Lou Y, Kou L, Yao Q, Chen R. Disulfiram and cancer immunotherapy: advanced nano-delivery systems and potential therapeutic strategies. International Journal of Pharmaceutics: X. 2024;8:100307.","journal-title":"International Journal of Pharmaceutics: X"},{"key":"3964_CR16","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/j.colsurfb.2017.08.037","volume":"160","author":"C Liu","year":"2017","unstructured":"Liu C, Lan Q, He W, Nie C, Zhang C, Xu T, et al. Octa-arginine modified lipid emulsions as a potential ocular delivery system for disulfiram: a study of the corneal permeation, transcorneal mechanism and anti-cataract effect. Colloids Surf B Biointerfaces. 2017;160:305\u201314.","journal-title":"Colloids Surf B Biointerfaces"},{"key":"3964_CR17","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00323","author":"P Desai","year":"2020","unstructured":"Desai P, Thumma NJ, Wagh PR, Zhan S, Ann D, Wang J, et al. Cancer chemoprevention using nanotechnology-based approaches. Front Pharmacol. 2020. https:\/\/doi.org\/10.3389\/fphar.2020.00323.","journal-title":"Front Pharmacol"},{"key":"3964_CR18","first-page":"73","volume":"13","author":"S Kovvasu","year":"2019","unstructured":"Kovvasu S, Kunamaneni P, Joshi R, Betageri G. Self-emulsifying drug delivery systems and their marketed products: a review. Asian J Pharm. 2019;13:73\u201384.","journal-title":"Asian J Pharm"},{"issue":"6","key":"3964_CR19","doi-asserted-by":"publisher","first-page":"675","DOI":"10.3109\/10717544.2014.896058","volume":"22","author":"S Dokania","year":"2015","unstructured":"Dokania S, Joshi AK. Self-microemulsifying drug delivery system (SMEDDS) \u2013 challenges and road ahead. Drug Deliv. 2015;22(6):675\u201390.","journal-title":"Drug Deliv"},{"key":"3964_CR20","doi-asserted-by":"publisher","first-page":"15","DOI":"10.14227\/DT180311P15","volume":"18","author":"MRC Marques","year":"2011","unstructured":"Marques MRC, Loebenberg R, Almukainzi M. Simulated biological fluids with possible application in dissolution testing. Dissolut Technol. 2011;18:15\u201328.","journal-title":"Dissolut Technol"},{"key":"3964_CR21","unstructured":"ICH. Stability testing of new drug substances and productsq1a(r2) 2003. Available from: https:\/\/database.ich.org\/sites\/default\/files\/Q1A%28R2%29%20Guideline.pdf. Accessed 25 Mar 2025."},{"key":"3964_CR22","doi-asserted-by":"publisher","first-page":"124568","DOI":"10.1016\/j.jchromb.2025.124568","volume":"1256","author":"M Komeno","year":"2025","unstructured":"Komeno M, Ohta A, Tanabe N, Abe H, Terashima Y, Saitoh A, et al. Determination of disulfiram and diethyldithiocarbamate in plasma by high performance liquid chromatography with an electrochemical detection using a diamond electrode. J Chromatogr B. 2025;1256:124568.","journal-title":"J Chromatogr B"},{"issue":"3","key":"3964_CR23","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/0006-2952(89)90380-8","volume":"38","author":"JJ Yourick","year":"1989","unstructured":"Yourick JJ, Faiman MD. Comparative aspects of disulfiram and its metabolites in the disulfiram-ethanol reaction in the rat. Biochem Pharmacol. 1989;38(3):413\u201321.","journal-title":"Biochem Pharmacol"},{"issue":"1","key":"3964_CR24","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/0016-5085(90)91288-H","volume":"98","author":"TY Ma","year":"1990","unstructured":"Ma TY, Hollander D, Krugliak P, Katz K. PEG 400, a hydrophilic molecular probe for measuring intestinal permeability. Gastroenterology. 1990;98(1):39\u201346.","journal-title":"Gastroenterology"},{"key":"3964_CR25","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics16060731","author":"D Yang","year":"2024","unstructured":"Yang D, Zhang M, Zhao M, Li C, Shang L, Zhang S, et al. Study on the effect of pharmaceutical excipient PEG400 on the pharmacokinetics of baicalin in cells based on MRP2, MRP3, and BCRP efflux transporters. Pharmaceutics. 2024. https:\/\/doi.org\/10.3390\/pharmaceutics16060731.","journal-title":"Pharmaceutics"},{"issue":"5","key":"3964_CR26","doi-asserted-by":"publisher","first-page":"285","DOI":"10.4274\/tjps.galenos.2022.73373","volume":"20","author":"R Nafiah","year":"2023","unstructured":"Nafiah R, Sumirtapura YC, Darijanto ST, Iwo MI. Development of the forskolin microemulsion formula and its irritation test on rabbits. Turk J Pharm Sci. 2023;20(5):285\u201393.","journal-title":"Turk J Pharm Sci"},{"issue":"1","key":"3964_CR27","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1021\/acs.molpharmaceut.2c00599","volume":"20","author":"P Szuma\u0142a","year":"2023","unstructured":"Szuma\u0142a P, Kapli\u0144ska J, Makurat-Kasprolewicz B, Mania S. Microemulsion delivery systems with low surfactant concentrations: optimization of structure and properties by glycol cosurfactants. Mol Pharm. 2023;20(1):232\u201340.","journal-title":"Mol Pharm"},{"key":"3964_CR28","unstructured":"PubChem. Sulfasalazine [03\/25\/2025]. Available from: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Salazopyrin ."},{"key":"3964_CR29","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics16020271","author":"MT Talianu","year":"2024","unstructured":"Talianu MT, Dinu-P\u00eervu CE, Ghica MV, Anu\u0163a V, Prisada RM, Popa L. Development and characterization of new Miconazole-based microemulsions for buccal delivery by implementing a full factorial design modeling. Pharmaceutics. 2024. https:\/\/doi.org\/10.3390\/pharmaceutics16020271.","journal-title":"Pharmaceutics"},{"key":"3964_CR30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jddst.2021.102416","volume":"63","author":"V Mohylyuk","year":"2021","unstructured":"Mohylyuk V, Pauly T, Dobrovolnyi O, Scott N, Jones DS, Andrews GP. Effect of carrier type and Tween\u00ae 80 concentration on the release of silymarin from amorphous solid dispersions. J Drug Deliv Sci Technol. 2021;63: 102416.","journal-title":"J Drug Deliv Sci Technol"},{"issue":"6","key":"3964_CR31","doi-asserted-by":"publisher","first-page":"1793","DOI":"10.1111\/j.1476-5381.2012.01887.x","volume":"166","author":"H Kusuhara","year":"2012","unstructured":"Kusuhara H, Furuie H, Inano A, Sunagawa A, Yamada S, Wu C, et al. Pharmacokinetic interaction study of sulphasalazine in healthy subjects and the impact of curcumin as an in vivo inhibitor of BCRP. Br J Pharmacol. 2012;166(6):1793\u2013803.","journal-title":"Br J Pharmacol"},{"issue":"8","key":"3964_CR32","doi-asserted-by":"publisher","DOI":"10.1002\/adtp.202300449","volume":"7","author":"DA Cooper","year":"2024","unstructured":"Cooper DA, Bhushan A. Bacterial influence on pharmacokinetics of tacrolimus and sulfasalazine through regulation of host metabolism. Adv Ther. 2024;7(8): 2300449.","journal-title":"Adv Ther"},{"key":"3964_CR33","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics13040559","author":"J Lee","year":"2021","unstructured":"Lee J, Kang J, Kwon NY, Sivaraman A, Naik R, Jin SY, et al. Dual inhibition of P-gp and BCRP improves oral topotecan bioavailability in rodents. Pharmaceutics. 2021. https:\/\/doi.org\/10.3390\/pharmaceutics13040559.","journal-title":"Pharmaceutics"}],"container-title":["Pharmaceutical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11095-025-03964-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11095-025-03964-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11095-025-03964-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T17:05:52Z","timestamp":1771347952000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11095-025-03964-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,16]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["3964"],"URL":"https:\/\/doi.org\/10.1007\/s11095-025-03964-7","relation":{},"ISSN":["0724-8741","1573-904X"],"issn-type":[{"value":"0724-8741","type":"print"},{"value":"1573-904X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,16]]},"assertion":[{"value":"28 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All experiments comply with the current laws of the country in which they were performed. All institutional and national guidelines for the care and use of laboratory animals were followed. The\n                      in vivo\n                      pharmacokinetic and lung tissue-biodistribution study protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Minnesota, USA (Protocol # 2206-40135A). No human studies were carried out by the authors for this article.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All authors declare no relevant financial or non-financial interests to disclose. All authors have approved the submission of this work for publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}