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Res."],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Modafinil is a well-established wake-promoting agent with emerging applications as a cognitive enhancer; however, its clinical potential is constrained by poor aqueous solubility and suboptimal systemic absorption, limiting effective brain delivery. This study presents transethosomes as a hitherto unexplored nanocarrier for modafinil and combines design-driven formulation with nuclear imaging-based biodistribution. Transethosomal vesicles were prepared using the ethanol injection method and systematically optimized through a 2\n                      <jats:sup>3<\/jats:sup>\n                      factorial design employing Design-Expert\n                      <jats:sup>\u00ae<\/jats:sup>\n                      software. Key formulation variables were investigated for their impact on EE%, PS, PDI, and ZP. Additionally, an in-vivo biodistribution and pharmacokinetic studies were conducted after labeling MOD with Technetium-99\u00a0m using sodium dithionite as a reducing agent. The optimized formulation achieved a high desirability value (0.919), superior EE% (85.87%), nanoscale PS (180.30\u00a0nm), and a negative ZP (\u2212\u200942.60\u00a0mV), indicative of excellent vesicular stability. Morphological and FTIR analyses confirmed spherical vesicles, drug\u2013excipient compatibility, and preservation of Modafinil\u2019s structure. In-vitro studies demonstrated a controlled biphasic release, supporting sustained drug availability, while stability assessments revealed no significant changes in vesicular characteristics over time. Ex-vivo studies highlighted markedly enhanced permeability, due to improved membrane fluidity and vesicle deformability from ethanol and the edge activator. The radiolabeling efficiency was high (92.18%), and it was stable for two hours. Biodistribution and pharmacokinetic studies confirmed significantly higher brain drug accumulation, elevated brain C\n                      <jats:sub>max<\/jats:sub>\n                      (5.4%ID\/g) and AUC, reduced T\n                      <jats:sub>max<\/jats:sub>\n                      (10\u00a0min) and high relative bioavailability (424.3\u2009\u00b1\u20094.5%). Importantly, histopathological examination of nasal mucosa revealed normal architecture. Collectively, these findings establish transethosomes as a promising and safe nano-platform for advanced brain targeting.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Modafinil-loaded transethosomes were designed as nanovesicles for brain targeting.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The optimized formulation showed spherical morphology, uniform size distribution, and strong drug\u2013carrier compatibility.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Stability studies confirmed preserved physicochemical properties throughout storage.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Ex-vivo permeation revealed significantly enhanced mucosal drug transport versus plain modafinil dispersion.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>In-vivo radio-distribution unambiguously confirmed superior uptake into the brain and improved targeting efficiency when contrasted with the reference preparation.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s13346-026-02103-y","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T12:49:04Z","timestamp":1776430144000},"page":"4309-4329","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Advanced modafinil-loaded transethosomes for brain targeting: development, ex-vivo permeation and radio-distribution evaluations"],"prefix":"10.1007","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1995-8537","authenticated-orcid":false,"given":"Marwa Eid","family":"Sayyed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0190-9502","authenticated-orcid":false,"given":"Sadek","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5884-4615","authenticated-orcid":false,"given":"Khaled M.","family":"Attallah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"issue":"4","key":"2103_CR1","doi-asserted-by":"publisher","first-page":"554","DOI":"10.4088\/jcp.v67n0406","volume":"67","author":"JS Ballon","year":"2006","unstructured":"Ballon JS, Feifel D. 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