{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T04:47:35Z","timestamp":1771390055235,"version":"3.50.1"},"reference-count":45,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,11,28]],"date-time":"2021-11-28T00:00:00Z","timestamp":1638057600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/04138\/2020 and UIDP\/04138\/2020"],"award-info":[{"award-number":["UIDB\/04138\/2020 and UIDP\/04138\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>Nanostructured lipid carriers (NLC) have been widely studied as delivery systems for a variety of routes, including the skin. Their composition results in an imperfect lipid matrix, allowing increased drug encapsulation. Allopurinol (AP), a xanthine oxidase inhibitor, is characterized by low water solubility and high melting point, which has hampered its use through the topical route. In this work, AP was incorporated in a NLC formulation to enhance drug-carrier association and skin delivery as a topical approach to treat wounds. AP-NLC system was characterized in terms of size, charge, rheological behavior, and in vitro skin permeation. The in vitro cytotoxicity was evaluated using HaCaT cells. The wound healing efficacy of the AP-NLC formulation on animal skin lesions was evaluated in male Wistar rats. The AP-NLC presented a mean size of 193 \u00b1 15 nm with a PdI of 0.240 \u00b1 0.02, zeta potential values around \u221249.6 mV, and an encapsulation efficiency of 52.2%. The AP-NLC formulation presented an adequate profile to be used topically, since epidermal and dermal drug retention were achieved. No reduction in HaCaT cells viability was observed at the tested concentrations (AP &lt; 10 \u03bcg\/mL). The in vivo application of the AP-NLC formulation resulted in the regeneration of skin lesions when compared with non-treated controls.<\/jats:p>","DOI":"10.3390\/bioengineering8120192","type":"journal-article","created":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T01:49:58Z","timestamp":1638150598000},"page":"192","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Topical Allopurinol-Loaded Nanostructured Lipid Carriers: A Novel Approach for Wound Healing Management"],"prefix":"10.3390","volume":"8","author":[{"given":"Carla","family":"Varrica","sequence":"first","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6028-4717","authenticated-orcid":false,"given":"Manuela","family":"Carvalheiro","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-2548","authenticated-orcid":false,"given":"Catarina","family":"Faria-Silva","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"given":"Carla","family":"Eleut\u00e9rio","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6766-9321","authenticated-orcid":false,"given":"Giuseppina","family":"Sandri","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy"}]},{"given":"Sandra","family":"Sim\u00f5es","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Quit\u00e9rio, M., Sim\u00f5es, S., Ascenso, A., Carvalheiro, M., Leandro, A.P., Correia, I., Viana, A.S., Fa\u00edsca, P., Ascens\u00e3o, L., and Molpeceres, J. (2021). Development of a Topical Insulin Polymeric Nanoformulation for Skin Burn Regeneration: An Experimental Approach. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084087"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1089\/wound.2015.0635","article-title":"Challenges in the Treatment of Chronic Wounds","volume":"4","author":"Frykberg","year":"2015","journal-title":"Adv. Wound Care"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Oliveira, A., Sim\u00f5es, S., Ascenso, A., and Reis, C.P. (2020). Therapeutic advances in wound healing. J. Dermatol. Treat., 1\u201321.","DOI":"10.1080\/09546634.2020.1730296"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1007\/s11926-013-0396-1","article-title":"Uric acid and xanthine oxidoreductase in wound healing","volume":"16","author":"Fernandez","year":"2014","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1111\/j.1742-481X.2011.00870.x","article-title":"Elevated uric acid correlates with wound severity","volume":"9","author":"Fernandez","year":"2012","journal-title":"Int. Wound J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1089\/wound.2016.0724","article-title":"Xanthine Oxidoreductase: A Novel Therapeutic Target for the Treatment of Chronic Wounds?","volume":"7","author":"Fernandez","year":"2018","journal-title":"Adv. Wound Care"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1124\/pr.58.1.6","article-title":"Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance Half a Century after the Discovery of Allopurinol","volume":"58","author":"Pacher","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"313","DOI":"10.2119\/molmed.2014.00191","article-title":"Xanthine Oxidoreductase Function Contributes to Normal Wound Healing","volume":"21","author":"Madigan","year":"2015","journal-title":"Mol. Med."},{"key":"ref_9","unstructured":"ClinicalTrials (2020, October 27). Effectiveness Allopurinol Topical Agent Prevention Capecitabine-induced Hand-foot Syndrome, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01609166."},{"key":"ref_10","unstructured":"Rodemer, Y., and Nobera Pharma SL (2013). Use of Allopurinol for the Treatment of Palmar Plantar Erythrodysesthesia. (US8557829B2), U.S. Patent."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1177\/112067210201200504","article-title":"Topical Allopurinol or Corticosteroids and Acetylcysteine in the Early Treatment of Experimental Corneal Alkali Burns: A Pilot Study","volume":"12","author":"Sekundo","year":"2002","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_12","first-page":"e250","article-title":"Tattoo skin reaction treatment with topical allopurinol: A good alternative","volume":"58","year":"2019","journal-title":"Int. J. Dermatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"113929","DOI":"10.1016\/j.addr.2021.113929","article-title":"Topical drug delivery: History, percutaneous absorption, and product development","volume":"177","author":"Roberts","year":"2021","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"640","DOI":"10.2174\/156720111797635487","article-title":"Topical Delivery of Antioxidants","volume":"8","author":"Ascenso","year":"2011","journal-title":"Curr. Drug Deliv."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2698","DOI":"10.2174\/1381612821666150428124053","article-title":"Overcoming the Skin Permeation Barrier: Challenges and Opportunities","volume":"21","author":"Vitorino","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"ref_16","first-page":"6577","article-title":"Lipid-Based Nanocarriers for Cutaneous Leishmaniais and Buruli Ulcer Management","volume":"22","author":"Carvalheiro","year":"2016","journal-title":"Curr. Pharm. Des."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1002\/nano.202000055","article-title":"Nanomaterials in wound healing: From material sciences to wound healing applications","volume":"1","author":"Barroso","year":"2020","journal-title":"Nano Sel."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S0939-6411(99)00076-4","article-title":"Allopurinol encapsulated in polycyanoacrylate nanoparticles as potential lysosomatropic carrier: Preparation and trypanocidal activity","volume":"49","author":"Figueroa","year":"2000","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1208\/s12249-020-01695-z","article-title":"Formulation, Optimization, and Evaluation of Allopurinol-Loaded Bovine Serum Albumin Nanoparticles for Targeting Kidney in Management of Hyperuricemic Nephrolithiasis","volume":"21","author":"Kandav","year":"2020","journal-title":"AAPS PharmSciTech"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"49","DOI":"10.22159\/ijap.2019v11i3.31932","article-title":"Formulation and evaluation of allopurinol loaded chitosan nanoparticles","volume":"11","author":"Kandav","year":"2019","journal-title":"Int. J. Appl. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.ijpharm.2004.12.027","article-title":"Effect of hexacosanol on the characteristics of novel sustained-release allopurinol solid lipospheres (SLS): Factorial design application and product evaluation","volume":"294","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"404","DOI":"10.2174\/1574885515666200120124214","article-title":"Allopurinol loaded transferosomes for the alleviation of symptomatic after-effects of Gout: An Account of Pharmaceutical implications","volume":"15","author":"Tiwari","year":"2020","journal-title":"Curr. Drug Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1080\/17425247.2020.1727883","article-title":"SLN and NLC for topical, dermal, and transdermal drug delivery","volume":"17","author":"Souto","year":"2020","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.ijpharm.2017.08.115","article-title":"Voriconazole-loaded nanostructured lipid carriers (NLC) for drug delivery in deeper regions of the nail plate","volume":"531","author":"Rocha","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_25","first-page":"13","article-title":"Effect of compositions in nanostructured lipid carriers (NLC) on skin hydration and occlusion","volume":"8","author":"Loo","year":"2013","journal-title":"Int. J. Nanomed."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.colsurfb.2018.01.053","article-title":"Development of nanoparticles from natural lipids for topical delivery of thymol: Investigation of its anti-inflammatory properties","volume":"164","author":"Pivetta","year":"2018","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.ijpharm.2013.05.017","article-title":"Budesonide-loaded nanostructured lipid carriers reduce inflammation in murine DSS-induced colitis","volume":"454","author":"Beloqui","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_28","unstructured":"Organisation for Economic Co-operation and Development (2004). OECD Guideline 428 for the Testing of Chemicals: Skin Absorption: In Vitro method, OECD."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.colsurfb.2016.07.021","article-title":"Ethosomes for enhanced skin delivery of griseofulvin","volume":"146","author":"Marto","year":"2016","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"De Souza Guedes, L., Martinez, R.M., Bou-Chacra, N.A., Velasco, M.V.R., Rosado, C., and Baby, A.R. (2021). An Overview on Topical Administration of Carotenoids and Coenzyme Q10 Loaded in Lipid Nanoparticles. Antioxidants, 10.","DOI":"10.3390\/antiox10071034"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1590\/S1984-82502011000300009","article-title":"Physicochemical characterization and solubility enhancement studies of allopurinol solid dispersions","volume":"47","author":"Changdeo","year":"2011","journal-title":"Braz. J. Pharm. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.ijpharm.2018.11.018","article-title":"smartPearls\u2014Novel physically stable amorphous delivery system for poorly soluble dermal actives","volume":"555","author":"Hespeler","year":"2019","journal-title":"Int. J. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1046\/j.1365-4362.2002.01555.x","article-title":"Correlation between pH and irritant effect of cleansers marketed for dry skin","volume":"41","author":"Baranda","year":"2002","journal-title":"Int. J. Dermatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1111\/j.1365-2133.2009.09168.x","article-title":"The effect of pH in modulating skin cell behaviour","volume":"161","author":"Sharpe","year":"2009","journal-title":"Br. J. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.ijpharm.2015.09.015","article-title":"Novel drug delivery strategies for improving econazole antifungal action","volume":"495","author":"Firooz","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_36","first-page":"23","article-title":"Formulation and in vitro characterization of domperidone loaded solid lipid nanoparticles and nanostructured lipid carriers","volume":"19","author":"Thatipamula","year":"2011","journal-title":"Daru"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.foodchem.2013.09.095","article-title":"Effect of aqueous pH and electrolyte concentration on structure, stability and flow behavior of non-ionic surfactant based solid lipid nanoparticles","volume":"147","author":"Choi","year":"2014","journal-title":"Food Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.ejps.2017.11.023","article-title":"Formulations based on solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for cutaneous use: A review","volume":"112","author":"Amaral","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3271","DOI":"10.2147\/DDDT.S264648","article-title":"Potential of Nanoparticles as Permeation Enhancers and Targeted Delivery Options for Skin: Advantages and Disadvantages","volume":"14","author":"Ghasemiyeh","year":"2020","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Mancini, G., Gon\u00e7alves, L.M.D., Marto, J., Carvalho, F.A., Sim\u00f5es, S., Ribeiro, H.M., and Almeida, A.J. (2021). Increased Therapeutic Efficacy of SLN Containing Etofenamate and Ibuprofen in Topical Treatment of Inflammation. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13030328"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.ijpharm.2015.11.050","article-title":"Rifabutin-loaded solid lipid nanoparticles for inhaled antitubercular therapy: Physicochemical and in vitro studies","volume":"497","author":"Gaspar","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ejps.2017.09.034","article-title":"Evaluation of critical parameters for in vitro skin permeation and penetration studies using animal skin models","volume":"111","author":"Medina","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1111\/wrr.12338","article-title":"The murine excisional wound model: Contraction revisited","volume":"23","author":"Chen","year":"2015","journal-title":"Wound Repair Regen."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.jconrel.2014.10.033","article-title":"The topical administration of rhEGF-loaded nanostructured lipid carriers (rhEGF-NLC) improves healing in a porcine full-thickness excisional wound model","volume":"197","author":"Gainza","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.immuni.2019.06.015","article-title":"The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair","volume":"51","author":"Kimball","year":"2019","journal-title":"Immunity"}],"container-title":["Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2306-5354\/8\/12\/192\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:36:57Z","timestamp":1760168217000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2306-5354\/8\/12\/192"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,28]]},"references-count":45,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["bioengineering8120192"],"URL":"https:\/\/doi.org\/10.3390\/bioengineering8120192","relation":{},"ISSN":["2306-5354"],"issn-type":[{"value":"2306-5354","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,28]]}}}