{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T15:01:54Z","timestamp":1785250914703,"version":"3.55.0"},"reference-count":24,"publisher":"American Chemical Society (ACS)","issue":"29","license":[{"start":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T00:00:00Z","timestamp":1783900800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda??o de Amparo ? i Pesquisa do Estado de S?o Paulo","doi-asserted-by":"publisher","award":["2022\/02193-0"],"award-info":[{"award-number":["2022\/02193-0"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior","doi-asserted-by":"publisher","award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Flubendazole (FLZ), a benzimidazole anthelmintic with emerging anticancer potential, exhibits poor aqueous solubility, limited oral bioavailability, and negligible spontaneous lymphatic transport. Building on previous work in which a Maisine CC-based FLZ nanoemulsion (FLZ-NE) was developed and shown to prevent the formation of malignant wounds in a murine model, this study provides a mechanistic pharmacokinetic evaluation of its intestinal lymphatic uptake. We investigated FLZ disposition in rats after oral administration of FLZ-NE, with or without cycloheximide pretreatment (FLZ-NE\/b) to inhibit chylomicron secretion. Plasma FLZ concentrations were quantified by a validated HPLC-UV method, and concentration-time data were analyzed by two-way ANOVA and noncompartmental analysis. FLZ-NE produced higher systemic exposure (C_max = 2.42 \u00b1 0.34 \u03bcg\/mL; T_max = 4 h; AUC_0 \u2013 t = 15.92 \u00b1 3.78 \u03bcg.h\/mL) than FLZ-NE\/b (C_max = 0.58 \u00b1 0.13 \u03bcg\/mL; T_max = 2 h; AUC_0 \u2013 t = 4.42 \u00b1 1.55 \u03bcg.h\/mL), corresponding to a 76% reduction in C_max and a 72% reduction in AUC_0 \u2013 t under chylomicron blockade. These data indicate that FLZ-NE relies predominantly on intestinal lymphatic transport, in line with the notion that long-chain fatty acid-based, nanoscale formulations can favor chylomicron-mediated uptake. By demonstrating in vivo that this nanoemulsion drives FLZ absorption through a lymphatic component, our findings extend the earlier efficacy-focused malignant wound study with mechanistic pharmacokinetic evidence of lymphatic targeting and support nanoemulsion-based delivery as a rational strategy to improve oral absorption and expand the therapeutic potential of FLZ for lymphatic or metastatic diseases.<\/jats:p>","DOI":"10.1021\/acsomega.6c02880","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T04:59:47Z","timestamp":1783918787000},"page":"43763-43769","source":"Crossref","is-referenced-by-count":0,"title":["Lymphatic Targeting\nof Flubendazole via Long-Chain\nFatty Acid Nanoemulsion: Pharmacokinetic Evidence of Chylomicron-Mediated\nUptake in Rats"],"prefix":"10.1021","volume":"11","author":[{"given":"Danielle Costa Vargas","family":"Redondo","sequence":"first","affiliation":[{"name":"University of Sa\u0303o Paulo , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 05508-010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6486-0470","authenticated-orcid":true,"given":"Je\u0301ssica Fagionato","family":"Masiero","sequence":"additional","affiliation":[{"name":"University of Sa\u0303o Paulo , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 05508-010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos Cecilio","family":"CostaJunior","sequence":"additional","affiliation":[{"name":"Federal University of Sa\u0303o Paulo , , , ,","place":["Diadema, Sa\u0303o Paulo, Brazil, 04023-062"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilly Costa de","family":"Oliveira","sequence":"additional","affiliation":[{"name":"University of Sa\u0303o Paulo , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 05508-010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmin da Silva","family":"Santos","sequence":"additional","affiliation":[{"name":"University of Sa\u0303o Paulo , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 05508-010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1826-7363","authenticated-orcid":true,"given":"Nikoletta","family":"Fotaki","sequence":"additional","affiliation":[{"name":"University of Bath , Claverton Down, ,","place":["Bath, Reino Unido, BA2 7AY"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raimar","family":"Lo\u0308benberg","sequence":"additional","affiliation":[{"name":"University of Alberta , , , ,","place":["Edmonton, Alberta, Canada, T6G 2T9"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7590-3587","authenticated-orcid":true,"given":"Gabriel Lima","family":"Barrosde Arau\u0301jo","sequence":"additional","affiliation":[{"name":"University of Sa\u0303o Paulo , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 05508-010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na\u0301dia Araci","family":"Bou-Chacra","sequence":"additional","affiliation":[{"name":"University of Sa\u0303o Paulo , , , ,","place":["Sa\u0303o Paulo, Sa\u0303o Paulo, Brazil, 05508-010"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandro Augusto","family":"Calixto","sequence":"additional","affiliation":[{"name":"Federal University of Sa\u0303o Paulo , , , ,","place":["Diadema, Sa\u0303o Paulo, Brazil, 04023-062"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,13]]},"reference":[{"issue":"4","key":"2026072810120469900_cit1","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.1152\/physrev.00039.2021","article-title":"Lymphatic vessels in\ncancer","volume":"102","author":"Dieterich","year":"2022","journal-title":"Physiol. Rev."},{"issue":"1","key":"2026072810120469900_cit2","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1007\/s10585-021-10123-w","article-title":"The lymphatic\nsystem and sentinel lymph nodes: conduit\nfor cancer metastasis","volume":"39","author":"Leong","year":"2022","journal-title":"Clin. Exp. Metastasis"},{"issue":"4","key":"2026072810120469900_cit3","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1007\/s10585-024-10288-0","article-title":"Cancer metastasis\nthrough the lymphatic versus blood\nvessels","volume":"41","author":"Leong","year":"2024","journal-title":"Clin. Exp. Metastasis"},{"issue":"2","key":"2026072810120469900_cit4","doi-asserted-by":"publisher","first-page":"14","DOI":"10.21037\/cco-20-205","article-title":"Pathophysiological\nand anatomical basis of lymphatic\ntransit of cancer cells and role of the lymphatic system: a review\nof published literature","volume":"10","author":"Matanes","year":"2021","journal-title":"Chin Clin Oncol"},{"issue":"1s","key":"2026072810120469900_cit5","doi-asserted-by":"publisher","first-page":"254s","DOI":"10.18433\/jpps30217","article-title":"Lymphatic Drug Absorption via the\nEnterocytes: Pharmacokinetic\nSimulation, Modeling, and Considerations for Optimal Drug Development","volume":"21","author":"Brocks","year":"2018","journal-title":"J. Pharm. Pharm. Sci."},{"key":"2026072810120469900_cit6","doi-asserted-by":"publisher","first-page":"533","DOI":"10.18433\/jpps32222","article-title":"The Lymphatic\nSystem: A Sometimes-Forgotten Compartment in Pharmaceutical Sciences","volume":"24","author":"Yousef","year":"2021","journal-title":"J. Pharm. Pharm. Sci."},{"issue":"9","key":"2026072810120469900_cit7","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1007\/s11095-020-02858-0","article-title":"Lymphatic\nTransport of Drugs after Intestinal Absorption: Impact of Drug Formulation\nand Physicochemical Properties","volume":"37","author":"Rys\u030ca\u0301nek","year":"2020","journal-title":"Pharm. Res."},{"issue":"4","key":"2026072810120469900_cit8","doi-asserted-by":"publisher","first-page":"293","DOI":"10.2217\/nnm-2023-0263","article-title":"Hydroxymethylnitrofurazone\nLymphatic Uptake\nwith Nanostructured Lipid Carrier After Oral Administration in Rats","volume":"19","author":"Souza","year":"2024","journal-title":"Nanomedicine"},{"key":"2026072810120469900_cit9","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3389\/fphar.2022.887402","article-title":"Targeting Lymphatics\nfor Nanoparticle Drug Delivery","volume":"13","author":"McCright","year":"2022","journal-title":"Front. Pharmacol."},{"key":"2026072810120469900_cit10","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1016\/j.jconrel.2020.10.036","article-title":"Targeted delivery of lopinavir to HIV reservoirs in\nthe mesenteric\nlymphatic system by lipophilic ester prodrug approach","volume":"329","author":"Qin","year":"2021","journal-title":"J. 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Bull."},{"issue":"7","key":"2026072810120469900_cit12","doi-asserted-by":"publisher","first-page":"1372","DOI":"10.3390\/pharmaceutics14071372","article-title":"Nanomaterial-Based\nDrug Delivery System Targeting Lymph Nodes","volume":"14","author":"Cheng","year":"2022","journal-title":"Pharmaceutics"},{"key":"2026072810120469900_cit13","doi-asserted-by":"publisher","first-page":"118189","DOI":"10.1016\/j.lfs.2020.118189","article-title":"Drug repurposing and\nrelabeling for cancer therapy:\nEmerging benzimidazole antihelminthics with potent anticancer effects","volume":"378","author":"Nath","year":"2025","journal-title":"Life Sci."},{"issue":"6","key":"2026072810120469900_cit14","doi-asserted-by":"publisher","first-page":"558","DOI":"10.3892\/ol.2024.14691","article-title":"Anticancer role of\nflubendazole: Effects and molecular mechanisms (Review)","volume":"28","author":"Xing","year":"2024","journal-title":"Oncol. Lett."},{"key":"2026072810120469900_cit15","unstructured":"Yukuyama, M. N.\n          \n          Repositioning\nstudy of flubendazole for treating lung cancer and meningoencephalitis\nusing an oral lipid nanosystem PhD Thsesis; Universidade de Sa\u0303o Paulo, 2023."},{"key":"2026072810120469900_cit16","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3389\/fonc.2022.990841","article-title":"Development\nof D-\u03b1-Tocopherol\npolyethylene glycol 1000 succinate fabricated nanostructural lipid\ncarrier of sorafenib tosylate for metastatic colorectal targeting\napplication: Stability, physical characterization, cytotoxicity, and\napoptotic studies against SW48 cells PTEN","volume":"12","author":"Bhattacharya","year":"2022","journal-title":"Front.\nOncol."},{"issue":"9","key":"2026072810120469900_cit17","doi-asserted-by":"publisher","first-page":"2782","DOI":"10.1016\/j.xphs.2016.03.003","article-title":"Evaluation of Three\nAmorphous Drug Delivery\nTechnologies to Improve the Oral Absorption of Flubendazole","volume":"105","author":"Vialpando","year":"2016","journal-title":"J. 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J.\nPharm."},{"issue":"12","key":"2026072810120469900_cit21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0261792","article-title":"Nanoemulsions\ncontaining Garcinia\nmangostana L. pericarp extract for topical applications: Development,\ncharacterization, and in vitro percutaneous penetration assay","volume":"16","author":"Krisanti","year":"2021","journal-title":"PLoS One"},{"key":"2026072810120469900_cit22","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1016\/j.jconrel.2021.12.003","article-title":"Smart design\napproaches for orally administered lipophilic prodrugs to promote\nlymphatic transport","volume":"341","author":"Elz","year":"2022","journal-title":"J. Controlled Release"},{"key":"2026072810120469900_cit23","doi-asserted-by":"publisher","first-page":"101899","DOI":"10.1016\/j.jddst.2020.101899","article-title":"Nano lipid\nbased carriers for lymphatic\nvoyage of anti-cancer drugs: An insight into the in-vitro, ex-vivo,\nin-situ and in-vivo study models","volume":"59","author":"Chaturvedi","year":"2020","journal-title":"J. Drug Delivery\nSci. Technol."},{"key":"2026072810120469900_cit24","doi-asserted-by":"publisher","first-page":"2733","DOI":"10.2147\/IJN.S41521","article-title":"Advanced drug delivery\nto the lymphatic system: Lipid-based nanoformulations","author":"Darwis","year":"2013","journal-title":"Int. J. Nanomed."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c02880","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/29\/43763\/65885303\/acsomega.6c02880.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/29\/43763\/65885303\/acsomega.6c02880.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T14:38:46Z","timestamp":1785249526000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/29\/43763\/5207072\/Lymphatic-Targeting-of-Flubendazole-via-Long-Chain"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,13]]},"references-count":24,"journal-issue":{"issue":"29","published-online":{"date-parts":[[2026,7,13]]},"published-print":{"date-parts":[[2026,7,28]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c02880","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,13]]}}}