{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T17:08:52Z","timestamp":1776100132319,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,24]],"date-time":"2020-12-24T00:00:00Z","timestamp":1608768000000},"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 a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/CTM-CTM\/30623\/2017"],"award-info":[{"award-number":["PTDC\/CTM-CTM\/30623\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UID\/CTM\/50025\/2019"],"award-info":[{"award-number":["UID\/CTM\/50025\/2019"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nanomaterials"],"abstract":"<jats:p>Several problems and limitations faced in the treatment of many diseases can be overcome by using controlled drug delivery systems (DDS), where the active compound is transported to the target site, minimizing undesirable side effects. In situ-forming hydrogels that can be injected as viscous liquids and jellify under physiological conditions and biocompatible clay nanoparticles have been used in DDS development. In this work, polymer\u2013clay composites based on Pluronics (F127 and F68) and nanoclays were developed, aiming at a biocompatible and injectable system for long-term controlled delivery of methylene blue (MB) as a model drug. MB release from the systems produced was carried out at 37 \u00b0C in a pH 7.4 medium. The Pluronic formulation selected (F127\/F68 18\/2 wt.%) displayed a sol\/gel transition at approx. 30 \u00b0C, needing a 2.5 N force to be injected at 25 \u00b0C. The addition of 2 wt.% of Na116 clay decreased the sol\/gel transition to 28 \u00b0C and significantly enhanced its viscoelastic modulus. The most suitable DDS for long-term application was the Na116-MB hybrid from which, after 15 days, only 3% of the encapsulated MB was released. The system developed in this work proved to be injectable, with a long-term drug delivery profile up to 45 days.<\/jats:p>","DOI":"10.3390\/nano11010025","type":"journal-article","created":{"date-parts":[[2020,12,24]],"date-time":"2020-12-24T09:02:44Z","timestamp":1608800564000},"page":"25","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["A New Long-Term Composite Drug Delivery System Based on Thermo-Responsive Hydrogel and Nanoclay"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6185-1958","authenticated-orcid":false,"given":"Cezar","family":"Tipa","sequence":"first","affiliation":[{"name":"CENIMAT\/I3N, Departamento de Ci\u00eancia dos Materiais, Faculdade de Ci\u00eancias e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8261-6754","authenticated-orcid":false,"given":"Maria T.","family":"Cidade","sequence":"additional","affiliation":[{"name":"CENIMAT\/I3N, Departamento de Ci\u00eancia dos Materiais, Faculdade de Ci\u00eancias e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal"}]},{"given":"T\u00e2nia","family":"Vieira","sequence":"additional","affiliation":[{"name":"CENIMAT\/I3N, Departamento de F\u00edsica, Faculdade de Ci\u00eancias e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9959-4272","authenticated-orcid":false,"given":"Jorge Carvalho","family":"Silva","sequence":"additional","affiliation":[{"name":"CENIMAT\/I3N, Departamento de F\u00edsica, Faculdade de Ci\u00eancias e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal"}]},{"given":"Paula I. P.","family":"Soares","sequence":"additional","affiliation":[{"name":"CENIMAT\/I3N, Departamento de Ci\u00eancia dos Materiais, Faculdade de Ci\u00eancias e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3996-6545","authenticated-orcid":false,"given":"Jo\u00e3o Paulo","family":"Borges","sequence":"additional","affiliation":[{"name":"CENIMAT\/I3N, Departamento de Ci\u00eancia dos Materiais, Faculdade de Ci\u00eancias e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.ijpharm.2014.06.029","article-title":"Thermoresponsive polymers: Insights into decisive hydrogel characteristics, mechanisms of gelation, and promising biomedical applications","volume":"472","author":"Kristl","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.colsurfb.2012.10.068","article-title":"The systems containing clays and clay minerals from modified drug release: A review","volume":"103","author":"Rodrigues","year":"2013","journal-title":"Colloid Surf. B"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"eaau6267","DOI":"10.1126\/scitranslmed.aau6267","article-title":"A gastric resident drug delivery system for prolonged gram-level dosing of tuberculosis treatment","volume":"11","author":"Verma","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.jsat.2020.01.009","article-title":"Perceptions and preferences for long-acting injectable and implantable medications in comparison to short-acting medications for opioid use disorders","volume":"111","author":"Saunders","year":"2020","journal-title":"J. Subst. Abuse Treat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.1021\/acsabm.9b00190","article-title":"Development of a long-term drug delivery system with levonorgestrel-loaded chitosan microspheres embedded in poly (vinyl alcohol) hydrogel","volume":"2","author":"Long","year":"2019","journal-title":"ACS Appl. Bio Mater."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"46068","DOI":"10.1002\/app.46068","article-title":"Biodegradable polymeric injectable implants for long-term delivery of contraceptive drugs","volume":"135","author":"Manoukian","year":"2018","journal-title":"J. Appl. Polym. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1007\/s11095-015-1686-2","article-title":"Long-acting injectable hormonal dosage forms for contraception","volume":"32","author":"Wu","year":"2015","journal-title":"Pharm. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.jconrel.2019.11.015","article-title":"Drug release testing of long-acting intrauterine systems","volume":"316","author":"Bao","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.biomaterials.2009.09.048","article-title":"The use of nanoparticle-mediated targeted gene silencing and drug delivery to overcome tumor drug resistance","volume":"31","author":"Patil","year":"2010","journal-title":"Biomaterials"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.schres.2016.11.010","article-title":"Does formulation matter? A systematic review and meta-analysis of oral versus long-acting antipsychotic studies","volume":"183","author":"Ostuzzi","year":"2017","journal-title":"Schizophr. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"108750","DOI":"10.1016\/j.biopha.2019.108750","article-title":"Strategies for the production of long-acting therapeutics and efficient drug delivery for cancer treatment","volume":"113","author":"AlQahtani","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.jconrel.2019.01.007","article-title":"Long-acting intraocular delivery strategies for biological therapy of age-related macular degeneration","volume":"296","author":"Iyer","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5399","DOI":"10.1016\/j.apsusc.2012.02.022","article-title":"Tio2 nanotube arrays deposited on ti substrate by anodic oxidation and their potential as a long-term drug delivery system for antimicrobial agents","volume":"258","author":"Moseke","year":"2012","journal-title":"Appl. Surf. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.ijpharm.2009.09.046","article-title":"Plga\/pva hydrogel composites for long-term inflammation control following s.C. Implantation","volume":"384","author":"Bhardwaj","year":"2010","journal-title":"Int. J. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s10544-011-9516-8","article-title":"Micro-fabricated perforated polymer devices for long-term drug delivery","volume":"13","author":"Wu","year":"2011","journal-title":"Biomed. Microdev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.addr.2018.03.007","article-title":"In situ forming injectable hydrogels for drug delivery and wound repair","volume":"127","author":"Dimatteo","year":"2018","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.eurpolymj.2015.03.016","article-title":"Injectable polymeric hydrogels for the delivery of therapeutic agents: A review","volume":"72","author":"Nguyen","year":"2015","journal-title":"Eur. Polym. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1016\/j.carbpol.2011.10.024","article-title":"\u0392-cyclodextrin hydrogels as potential drug delivery systems","volume":"87","author":"Isasi","year":"2012","journal-title":"Carbohydr. Polym."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.jddst.2018.09.004","article-title":"Development and evaluation of thermo-sensitive hydrogel system with nanocomplexes for prolonged subcutaneous delivery of enoxaparin","volume":"48","author":"Fang","year":"2018","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.msec.2017.05.096","article-title":"A mini review on hydrogels classification and recent developments in miscellaneous applications","volume":"79","author":"Varaprasad","year":"2017","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.carbpol.2016.08.068","article-title":"Thermo-sensitive injectable hydrogel based on the physical mixing of hyaluronic acid and pluronic f-127 for sustained nsaid delivery","volume":"156","author":"Jung","year":"2017","journal-title":"Carbohydr. Polym."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.mtchem.2018.02.004","article-title":"Hydrogels as intelligent materials: A brief review of synthesis, properties and applications","volume":"8","author":"Mahinroosta","year":"2018","journal-title":"Mater. Today Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.addr.2009.07.019","article-title":"Chitosan-based hydrogels for controlled, localized drug delivery","volume":"62","author":"Bhattarai","year":"2010","journal-title":"Adv. Drug Deliver. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S0169-409X(02)00018-2","article-title":"Pluronic block copolymers: Novel functional molecules for gene therapy","volume":"54","author":"Kabanov","year":"2002","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.biomaterials.2017.12.024","article-title":"Clay nanoparticles for regenerative medicine and biomaterial design: A review of clay bioactivity","volume":"159","author":"Mousa","year":"2018","journal-title":"Biomaterials"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1016\/j.progpolymsci.2008.07.008","article-title":"A review on polymer\u2013layered silicate nanocomposites","volume":"33","author":"Pavlidou","year":"2008","journal-title":"Prog. Polym. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.progpolymsci.2018.07.003","article-title":"Polymer nanocomposites based on silylated-montmorillonite: A review","volume":"85","author":"Bee","year":"2018","journal-title":"Prog. Polym. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.compositesb.2012.04.012","article-title":"Epoxy clay nanocomposites\u2014processing, properties and applications: A review","volume":"45","author":"Azeez","year":"2013","journal-title":"Compos. Part B Eng."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1179\/174328408X341708","article-title":"Biopolymer\u2013clay nanocomposites for controlled drug delivery","volume":"24","author":"Viseras","year":"2008","journal-title":"Mater. Sci. Technol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.clay.2006.06.015","article-title":"Use of clays as drug delivery systems: Possibilities and limitations","volume":"36","author":"Aguzzi","year":"2007","journal-title":"Appl. Clay Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.clay.2016.01.021","article-title":"Drug\u2013clay nanohybrids as sustained delivery systems","volume":"130","author":"Yang","year":"2016","journal-title":"Appl. Clay Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"50002","DOI":"10.1039\/C6RA03942A","article-title":"Clay nanocomposites as engineered drug delivery systems","volume":"6","author":"Jafarbeglou","year":"2016","journal-title":"RSC Adv."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.micromeso.2018.03.017","article-title":"Extended-release of chlorpromazine intercalated into montmorillonite clays","volume":"267","author":"Djebbi","year":"2018","journal-title":"Microporous Mesoporous Mater."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.jddst.2018.06.007","article-title":"Synthesis, characterization and chlorhexidine release from either montmorillonite or palygorskite modified organoclays for antibacterial applications","volume":"46","year":"2018","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_35","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":"Ozhmukhametova","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_36","first-page":"152","article-title":"Intercalation of methylene blue into montmorillonite at different conditions: An approach for preparing clay-based nanopigments","volume":"56","author":"Mazdak","year":"2012","journal-title":"Ceramics-Silik\u00e1ty"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.jcis.2018.02.004","article-title":"Effect of intercalated chitosan\/clay nanostructures on concentrated pluronic f127 solution: A ftir-atr, dsc and rheological study","volume":"517","author":"Branca","year":"2018","journal-title":"J. Colloid Interface Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.ijpharm.2013.01.043","article-title":"Nanostructured fluids from pluronic\u00ae mixtures","volume":"454","author":"Zhang","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.jddst.2017.12.002","article-title":"Investigation of effectiveness of some extensively used polymers on thermoreversible properties of pluronic\u00ae tri-block copolymers","volume":"44","author":"Rarokar","year":"2018","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.colsurfa.2015.08.034","article-title":"Molecular interactions between peo\u2013ppo\u2013peo and ppo\u2013peo\u2013ppo triblock copolymers in aqueous solution","volume":"484","author":"Liu","year":"2015","journal-title":"Colloids Surf. A Physicochem. Eng. Asp."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3561","DOI":"10.1016\/j.polymer.2008.05.038","article-title":"The effect of physiologically relevant additives on the rheological properties of concentrated pluronic copolymer gels","volume":"49","author":"Jiang","year":"2008","journal-title":"Polymer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.msea.2011.09.020","article-title":"Effect of clay organic modifier on the final performance of pcl\/clay nanocomposites","volume":"529","author":"Kenny","year":"2011","journal-title":"Mater. Sci. Eng. A"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.tca.2007.03.008","article-title":"Thermal degradation of commercially available organoclays studied by tga\u2013ftir","volume":"457","author":"Paul","year":"2007","journal-title":"Thermochim. Acta"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.carbpol.2018.02.045","article-title":"Physical characterization and modeling of chitosan\/peg blends for injectable scaffolds","volume":"189","author":"Lima","year":"2018","journal-title":"Carbohydr. Polym."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1021\/cm0217194","article-title":"Effects of solvent solubility parameters on organoclay dispersions","volume":"15","author":"Ho","year":"2003","journal-title":"Chem. Mater."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jcis.2004.05.015","article-title":"Solvent-based nanocomposite coatings: I. Dispersion of organophilic montmorillonite in organic solvents","volume":"278","author":"Duchet","year":"2004","journal-title":"J. Colloid Interface Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1208\/s12248-010-9185-1","article-title":"Ddsolver: An add-in program for modeling and comparison of drug dissolution profiles","volume":"12","author":"Zhang","year":"2010","journal-title":"AAPS J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.carbpol.2016.03.028","article-title":"Chitosan-based nanoparticles as drug delivery systems for doxorubicin: Optimization and modelling","volume":"147","author":"Soares","year":"2016","journal-title":"Carbohydr. Polym."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.carbpol.2016.07.109","article-title":"Towards the development of multifunctional chitosan-based iron oxide nanoparticles: Optimization and modelling of doxorubicin release","volume":"153","author":"Soares","year":"2016","journal-title":"Carbohydr. Polym."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0378-5173(89)90306-2","article-title":"A simple equation for the description of solute release. Iii. Coupling of diffusion and relaxation","volume":"57","author":"Peppas","year":"1989","journal-title":"Int. J. Pharm."},{"key":"ref_51","first-page":"217","article-title":"Kinetic modeling on drug release from controlled drug delivery systems","volume":"67","author":"Dash","year":"2010","journal-title":"Acta Pol. Pharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ijpharm.2005.10.044","article-title":"On the use of the weibull function for the discernment of drug release mechanisms","volume":"309","author":"Papadopoulou","year":"2006","journal-title":"Int. J. Pharm."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"258","DOI":"10.3389\/fbioe.2020.00258","article-title":"A methodological safe-by-design approach for the development of nanomedicines","volume":"8","author":"Schmutz","year":"2020","journal-title":"Front. Bioeng. Biotechnol."}],"container-title":["Nanomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-4991\/11\/1\/25\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:45:39Z","timestamp":1760179539000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-4991\/11\/1\/25"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,24]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["nano11010025"],"URL":"https:\/\/doi.org\/10.3390\/nano11010025","relation":{},"ISSN":["2079-4991"],"issn-type":[{"value":"2079-4991","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,24]]}}}