{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:09:09Z","timestamp":1788786549488,"version":"build-2803163510"},"reference-count":163,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004242","name":"Princess Nourah bint Abdulrahman University","doi-asserted-by":"publisher","award":["PNURSP2026R340"],"award-info":[{"award-number":["PNURSP2026R340"]}],"id":[{"id":"10.13039\/501100004242","id-type":"DOI","asserted-by":"publisher"}]},{"award":["PNURSP2026R340"],"award-info":[{"award-number":["PNURSP2026R340"]}],"id":[{"id":"https:\/\/ror.org\/05b0cyh02","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Repurposing existing drugs may represent a promising strategy for effective cancer therapy. This study was the first to investigate the augmented antitumor therapeutic effect achieved by co-incorporating the NSAID Niflumic acid (NIF) with ceramides into PEGylated cerosomes (NIF-loaded PEG-CERs) in a novel platform that targets specifically the MAPK-ERK signaling pathway and miR-21-5p modulation. Methods: The prepared formulae were statistically optimized utilizing a full factorial design and the optimal formula (C5) was further incorporated into a topical gel and evaluated for ex vivo rat skin permeation, and tested in vivo in a subcutaneous solid Ehrlich carcinoma (SEC) mice model. Results: The optimal formula (C5) showed tubular elongated morphology with higher EE% (96.71 \u00b1 0.0), lower vesicular size (VS) and PDI values, 292.95 \u00b1 0.78 nm and 0.47 \u00b1 0.0 respectively. A high ZP value (\u221237.5 \u00b1 0.57 mV) was in accordance with stability results showing good stability of the optimal formula (C5). Permeability studies exhibited 2.02-fold higher skin permeation compared to pure NIF gel. A significant decrease in tumor volume and marked improvement in survival rate in SEC mice were confirmed by downregulation of EGFR, ERK1, ERK2, and miR-21-5p expression. Furthermore, an increase in total antioxidant capacity and caspase-3 levels was observed, accompanied by significant suppression in cyclin D1, MMP-2, COX-2, and MDA levels. Finally, histopathological analysis revealed the superior antitumor effect of C5 gel together with immunohistochemical assay showing the lowest BCL-2-positive staining, indicating the restoration of physiological apoptotic balance. Conclusions: Based on the previous findings, NIF-loaded PEG-CERs offer augmented therapeutic potential for efficient topical skin cancer management in an SEC mice model.<\/jats:p>","DOI":"10.3390\/pharmaceutics18091125","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:12:25Z","timestamp":1788783145000},"page":"1125","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Repurposing Niflumic Acid-Loaded PEGylated Cerosomes for Topical Solid Ehrlich\u2019s Carcinoma Management via EGFR\/ERK\/miR-21 Signaling Pathway Modulation"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7970-8732","authenticated-orcid":false,"given":"Mona M.","family":"Mostafa","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October 6 University, 6th of October City, Giza 12585, Egypt"},{"name":"Postgraduate Researcher, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3980-719X","authenticated-orcid":false,"given":"Shaimaa","family":"Mosallam","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October 6 University, 6th of October City, Giza 12585, 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Egypt"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1719-1797","authenticated-orcid":false,"given":"Maha M.","family":"Amin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1776-9249","authenticated-orcid":false,"given":"Jawaher Abdullah","family":"Alamoudi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6973-6460","authenticated-orcid":false,"given":"Heba Mohammed Refat M.","family":"Selim","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Diriyah, Riyadh 13713, Saudi Arabia"},{"name":"Research Center, Deanship of Scientific Research and Post-Graduate Studies, AlMaarefa University, Diriyah, Riyadh 13713, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0663-0893","authenticated-orcid":false,"given":"Mira Magdy","family":"William","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, October 6 University, 6th of October City, Giza 12585, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2716-4676","authenticated-orcid":false,"given":"Shady M.","family":"Abd El-Halim","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October 6 University, 6th of October City, Giza 12585, 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