{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:27:31Z","timestamp":1790684851137,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,10,15]],"date-time":"2019-10-15T00:00:00Z","timestamp":1571097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007364","name":"Fondazione CRT","doi-asserted-by":"publisher","award":["2017.0820"],"award-info":[{"award-number":["2017.0820"]}],"id":[{"id":"10.13039\/100007364","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nanomaterials"],"abstract":"<jats:p>Endophthalmitis is a rare, but serious, intravitreal inflammatory disorder that can arise after cataract surgery. The intracameral injection of 1 mg cefuroxime (CEF) followed by three-times daily antibiotic topical administration for a week is generally recognized as the routine method of prophylaxis after cataract surgery. This procedure is controversial because of both the low efficacy and the low adherence to therapy by elderly patients. A unique slow release antibiotic intravitreal injection could solve these problems. The objective of the present study was to design ophthalmic nanocomposite delivery systems based on in situ gelling formulations that undergo sol-to-gel transition upon change in temperature to prolong the effect of CEF. Oil in water (O\/W) microemulsion (\u00b5E) and solid lipid nanoparticles (SLN), obtained with an innovative formulation technology called cold microemulsion dilution, were evaluated as ocular drug delivery systems for CEF. Drug entrapment efficiency up to 80% was possible by esterifying CEF with 1-dodecanol to obtain dodecyl-CEF (dCEF). Both dCEF-loaded SLN and \u00b5E were then added with Pluronic\u00aeF127 (20% w\/v) to obtain a nanocomposite hydrogel-based long acting system. The prepared thermosensitive formulations were evaluated for their physical appearance, drug content, gelation temperature, injectability and rheological properties, in vitro release studies and stability studies. Moreover, cell proliferation assays on human retinal pigment epithelial ARPE-19 cells were performed to evaluate the influence of this innovative system on the cellular viability. In addition, minimal inhibitory concentration (MIC) was assessed for both CEF and dCEF, revealing the need of dCEF hydrolysis for the antimicrobial activity. Although further experimental investigations are required, the physico-chemical characterization of the nanocomposite hydrogels and the preliminary in vitro release studies highlighted the potential of these systems for the sustained release of CEF.<\/jats:p>","DOI":"10.3390\/nano9101461","type":"journal-article","created":{"date-parts":[[2019,10,16]],"date-time":"2019-10-16T03:32:54Z","timestamp":1571196774000},"page":"1461","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Thermosensitive Nanocomposite Hydrogels for Intravitreal Delivery of Cefuroxime"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5335-8442","authenticated-orcid":false,"given":"Simona","family":"Sapino","sequence":"first","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8017-4956","authenticated-orcid":false,"given":"Elena","family":"Peira","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4615-5812","authenticated-orcid":false,"given":"Daniela","family":"Chirio","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Chindamo","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Guglielmo","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simonetta","family":"Oliaro-Bosso","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4497-6382","authenticated-orcid":false,"given":"Raffaella","family":"Barbero","sequence":"additional","affiliation":[{"name":"SC of Serology, Istituto Zooprofilattico Sperimentale Piemonte Liguria e Valle d\u2019Aosta, 10154 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7766-4647","authenticated-orcid":false,"given":"Cristina","family":"Vercelli","sequence":"additional","affiliation":[{"name":"Department of Veterinary Sciences of Turin, University of Turin, 10095 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Re","sequence":"additional","affiliation":[{"name":"Department of Veterinary Sciences of Turin, University of Turin, 10095 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Brunella","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Turin, 10125 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Riedo","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Turin, 10125 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio Maria","family":"Fea","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Gallarate","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Garhart, C., and Lakshminarayanan, V. (2016). Anatomy of the eye. Handbook of Visual Display Technology, Springer.","DOI":"10.1007\/978-3-319-14346-0_4"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.jconrel.2014.05.031","article-title":"Nanotherapy for posterior eye diseases","volume":"193","author":"Kaur","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e1221","DOI":"10.1016\/S2214-109X(17)30393-5","article-title":"Global causes of blindness and distance vision impairment 1990\u20132020: A systematic review and meta-analysis","volume":"5","author":"Flaxman","year":"2017","journal-title":"Lancet Glob. Heal."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1002\/wnan.1473","article-title":"Nanocarrier mediated retinal drug delivery: Overcoming ocular barriers to treat posterior eye diseases","volume":"10","author":"Bisht","year":"2018","journal-title":"Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.drudis.2007.11.002","article-title":"Current and future ophthalmic drug delivery systems. A shift to the posterior segment","volume":"13","author":"Urtti","year":"2008","journal-title":"Drug Discov. Today"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1097\/ICU.0b013e3281108000","article-title":"Drug delivery methods for posterior segment disease","volume":"18","author":"Hsu","year":"2007","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1080\/21691401.2018.1478845","article-title":"Polymeric, injectable, intravitreal hydrogel devices for posterior segment applications and interventions","volume":"46","author":"Anwary","year":"2018","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.ejpb.2016.10.013","article-title":"Lipid nanoparticles (SLN, NLC): Overcoming the anatomical and physiological barriers of the eye\u2013Part II-Ocular drug-loaded lipid nanoparticles","volume":"110","author":"Espina","year":"2017","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S0378-5173(02)00080-7","article-title":"Solid lipid nanoparticles (SLN) as ocular delivery system for tobramycin","volume":"238","author":"Cavalli","year":"2002","journal-title":"Int. J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S1773-2247(12)50016-X","article-title":"Solid lipid nanoparticles prepared by coacervation method as vehicles for ocular cyclosporine","volume":"22","author":"Battaglia","year":"2012","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1080\/17425247.2016.1227783","article-title":"Recent perspectives on the delivery of biologics to back of the eye","volume":"14","author":"Joseph","year":"2017","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.ijpharm.2012.10.015","article-title":"Development of O\/W nanoemulsions for ophthalmic administration of timolol","volume":"440","author":"Gallarate","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1080\/02652048.2018.1425750","article-title":"Microemulsion-based delivery of triamcinolone acetonide to posterior segment of eye using chitosan and butter oil as permeation enhancer: An in vitro and in vivo investigation","volume":"35","author":"Raval","year":"2018","journal-title":"J. Microencapsul."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/0378-5173(93)90094-V","article-title":"Preparation and evaluation in vitro of solutions and O\/W microemulsions containing levobunolol as ion-pair","volume":"100","author":"Gallarate","year":"1993","journal-title":"Int. J. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hegde, R.R., Verma, A., and Ghosh, A. (2013). Microemulsion: New Insights into the Ocular Drug Delivery. ISRN Pharm.","DOI":"10.1155\/2013\/826798"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.joco.2016.05.002","article-title":"Post-cataract surgery endophthalmitis: Brief literature review","volume":"28","author":"Hashemian","year":"2016","journal-title":"J. Curr. Ophthalmol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Gower, E.W., Lindsley, K., Tulenko, S.E., Nanji, A.A., Leyngold, I., and Mcdonnell, P.J. (2017). Perioperative antibiotics for prevention of acute endophthalmitis after cataract surgery. Cochrane Database Syst. Rev., 1\u201345.","DOI":"10.1002\/14651858.CD006364.pub3"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1097\/ICB.0000000000000577","article-title":"Ocular toxicity after inadvertent intracameral injection of high dose of cefuroxime during cataract surgery: A case series","volume":"13","author":"Osoba","year":"2019","journal-title":"Retin Cases Brief. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1001\/jamaophthalmol.2015.2421","article-title":"Transient macular edema after intracameral injection of a moderately elevated dose of cefuroxime during phacoemulsification surgery","volume":"133","author":"Wong","year":"2015","journal-title":"JAMA Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Jairam, R.K., Mallurwar, S.R., Gabani, B.B., Zakkula, A., Kiran, V., Dittakavi, S., Sulochana, S.P., Mohd, Z., Srinivas, N.R., and Mullangi, R. (2019). Uptake and pharmacokinetics of cefuroxime in rabbits after intravitreal, intracameral, and topical dosing: Relevance to human ocular injection of cefuroxime. Xenobiotica, 1\u20137.","DOI":"10.1080\/00498254.2019.1624872"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/S0731-7085(00)00306-X","article-title":"First-derivative spectrophotometric and LC determination of cefuroxime and cefadroxil in urine","volume":"23","author":"Bedair","year":"2000","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S1773-2247(11)50080-2","article-title":"Thermogelling microemulsions for topical delivery of griseofulvin","volume":"21","author":"Peira","year":"2011","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Chirio, D., Peira, E., Sapino, S., Dianzani, C., Barge, A., Muntoni, E., Morel, S., and Gallarate, M. (2018). Stearoyl-chitosan coated nanoparticles obtained by microemulsion cold dilution technique. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19123833"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Chirio, D., Peira, E., Dianzani, C., Muntoni, E., Gigliotti, C., Ferrara, B., Sapino, S., Chindamo, G., and Gallarate, M. (2019). Development of Solid Lipid Nanoparticles by Cold Dilution of Microemulsions: Curcumin Loading, Preliminary In Vitro Studies, and Biodistribution. Nanomaterials, 9.","DOI":"10.3390\/nano9020230"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1089\/ten.2005.11.974","article-title":"Pluronic F127 as a Cell Encapsulation Material: Utilization of Membrane-Stabilizing Agents","volume":"11","author":"Khattak","year":"2005","journal-title":"Tissue Eng."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3330","DOI":"10.1002\/jps.24480","article-title":"The PK-Eye: A Novel in Vitro Ocular Flow Model for Use in Preclinical Drug Development","volume":"104","author":"Awwad","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kummer, M.P., Abbott, J.J., Dinser, S., and Nelson, B.J. (2007, January 23\u201326). Artificial vitreous humor for in Vitro experiments. Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology, Lyon, France.","DOI":"10.1109\/IEMBS.2007.4353822"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ejpb.2014.11.022","article-title":"Mesoporous silica as topical nanocarriers for quercetin: Characterization and in vitro studies","volume":"89","author":"Sapino","year":"2015","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.ijpharm.2016.07.024","article-title":"Thermoresponsive mesoporous silica nanoparticles as a carrier for skin delivery of quercetin","volume":"511","author":"Ugazio","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.ijpharm.2017.07.058","article-title":"Mesoporous silica nanoparticles as a promising skin delivery system for methotrexate","volume":"530","author":"Sapino","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1046\/j.0269-4727.2003.00503.x","article-title":"Stability of reconstituted parecoxib for injection with commonly used diluents","volume":"28","author":"Crane","year":"2003","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1002\/jps.2600651104","article-title":"Comparative stability of cephalosporins in aqueous solution: Kinetics and mechanisms of degradation","volume":"65","author":"Yamana","year":"1976","journal-title":"J. Pharm. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/j.1365-2710.1986.tb00827.x","article-title":"Stability of cefuroxime sodium in some aqueous buffered solutions and intravenous admixtures","volume":"11","author":"Stewart","year":"1986","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/1559-0275-11-29","article-title":"Proteomic analysis of human vitreous humor","volume":"11","author":"Murthy","year":"2014","journal-title":"Clin. Proteomics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S0378-5173(03)00135-2","article-title":"Preparation of solid lipid nanoparticles by a solvent emulsification-diffusion technique","volume":"257","author":"Trotta","year":"2003","journal-title":"Int. J. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/0927-7765(94)80063-4","article-title":"Thermoanalysis of the recrystallization process of melt-homogenized glyceride nanoparticles","volume":"3","author":"Siekmann","year":"1994","journal-title":"Colloids Surf. B"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1016\/S0142-9612(02)00578-1","article-title":"The production and characteristics of solid lipid nanoparticles (SLNs)","volume":"24","author":"Hou","year":"2003","journal-title":"Biomaterials"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.ijpharm.2007.03.009","article-title":"Solid lipid nanoparticles loaded with insulin by sodium cholate-phosphatidylcholine-based mixed micelles: Preparation and characterization","volume":"340","author":"Liu","year":"2007","journal-title":"Int. J. Pharm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1208\/s12249-011-9625-y","article-title":"Injectability Evaluation: An Open Issue","volume":"12","author":"Cilurzo","year":"2011","journal-title":"AAPS PharmSciTech"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1002\/mabi.201100265","article-title":"Synthesis and Characterization of a Multi-Sensitive Crosslinked Injectable Hydrogel Based on Pluronic","volume":"11","author":"Nam","year":"2011","journal-title":"Macromol. Biosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.jconrel.2017.10.031","article-title":"Injectable hydrogels for ophthalmic applications","volume":"268","author":"Wang","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1016\/j.msec.2016.05.119","article-title":"Solid lipid nanoparticles as attractive drug vehicles: Composition, properties and therapeutic strategies","volume":"68","author":"Moritz","year":"2016","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.ijpharm.2016.02.027","article-title":"In situ gelling systems based on Pluronic F127\/Pluronic F68 formulations for ocular drug delivery","volume":"502","author":"Khateba","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1080\/109158101529025921","article-title":"Final report on the safety assessment of trilaurin, triarachidin, tribehenin, tricaprin, tricaprylin, trierucin, triheptanoin, triheptylundecanoin, triisononanoin, triisopalmitin, triisostearin, trilinolein, trimyristin, trioctanoin, triolein, tripalmitin, tripalmitolein, triricinolein, tristearin, triundecanoin, glyceryl triacetyl hydroxystearate, glyceryl triacetyl ricinoleate, and glyceryl stearate diacetate","volume":"20","author":"Johnson","year":"2001","journal-title":"Int J. Toxicol."}],"container-title":["Nanomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-4991\/9\/10\/1461\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:26:35Z","timestamp":1760189195000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-4991\/9\/10\/1461"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,15]]},"references-count":44,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["nano9101461"],"URL":"https:\/\/doi.org\/10.3390\/nano9101461","relation":{},"ISSN":["2079-4991"],"issn-type":[{"value":"2079-4991","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,15]]}}}