{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:02:19Z","timestamp":1789981339483,"version":"4.0.1"},"reference-count":44,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"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: Diabetes-associated wound healing is frequently impaired due to persistent hyperglycemia, which causes vascular dysfunction and neuropathy, thereby delaying tissue repair. Objectives: In this study, hyaluronic acid and protamine nanoparticles (HA-PRO-NPs) were developed and optimized to encapsulate disulfiram (DSF) and coumarin (COM) for potential application in diabetic wound healing. Methods: The nanoparticles were prepared using a simple ionic interaction method and characterized for their particle size, zeta potential, morphology and encapsulation efficiency. Then, HA-PRO-NPs were incorporated into a hydrogel that contains carboxymethyl cellulose (CMC) and propylene glycol (PG). The hydrogel formulations were evaluated for swelling behavior, spreadability and DSF and COM release kinetics. Results: The prepared formulations were safe against human dermal fibroblasts (HDFs), with cell viability remaining above 70% over the concentration ranges tested. In the scratch assay, HA-PROT-DSF-COM-NPs improved HDF migration, achieving approximately 81% wound closure. An in vivo study was conducted using streptozotocin-induced diabetic mice. Topical application of Gel-HA-PROT-DSF-COM-NPs promoted wound closure. The study monitored wound contraction on Days 0, 3, 7, and 12. By Day 12, topical administration of the dual-cargo system (Gel-HA-PROT-DSF-COM NPs, n = 6) achieved 78.2 \u00b1 4.1% wound closure. This was significantly higher than the single-drug formulation (Gel-HA-PROT-DSF-NPs: 59.5 \u00b1 4.8%) and the untreated Control (Diabetic) group (55.4 \u00b1 5.2%, p &lt; 0.01), while the non-diabetic Control group (non diabetic) reached 97.6 \u00b1 3.5% closure. Semi-quantitative histopathological evaluation showed that the Gel-HA-PROT-DSF-COM NPs achieved a healing score of 4\/5, characterized by optimized epidermal regeneration with preserved adnexal structures and moderate dermal remodeling. Conclusions: In conclusion, Gel-HA-PROT-DSF-COM-NPs demonstrated promising potential as a topical formulation for improving wound healing under diabetic conditions.<\/jats:p>","DOI":"10.3390\/pharmaceutics18091180","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:03:47Z","timestamp":1789977827000},"page":"1180","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development and Characterization of a Hydrogel Incorporating Protamine\u2013Hyaluronic Acid Nanoparticles Co-Loaded with Disulfiram and Coumarin for Diabetic Wound Healing"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2847-2416","authenticated-orcid":false,"given":"Zainab","family":"Lafi","sequence":"first","affiliation":[{"name":"Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan"},{"name":"Department of Pharmaceutics and Pharmaceutical Technology, Al-Ahliyya Amman University, Amman 19328, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Mohammad I. A.","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan"},{"name":"Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman 19328, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreen Deeb","family":"Nusair","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0103-1058","authenticated-orcid":false,"given":"Razan","family":"Madi","sequence":"additional","affiliation":[{"name":"Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2305-375X","authenticated-orcid":false,"given":"Alaa","family":"Al-Sanabrah","sequence":"additional","affiliation":[{"name":"Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somaya","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Qout","family":"Qtashat","sequence":"additional","affiliation":[{"name":"Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8685-7471","authenticated-orcid":false,"given":"Maisrh Ali","family":"Alrubaye","sequence":"additional","affiliation":[{"name":"Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3336-3112","authenticated-orcid":false,"given":"Sara Yousef","family":"Asha","sequence":"additional","affiliation":[{"name":"School of Medicine, Jordan University, Amman 19328, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.jtv.2023.01.010","article-title":"Effectiveness of hyaluronic acid in post-surgical cures following partial matricectomies with the phenol\/alcohol technique: A randomized clinical trial","volume":"32","year":"2023","journal-title":"J. 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