{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:48:19Z","timestamp":1785422899233,"version":"3.56.0"},"reference-count":51,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 AR080500"],"award-info":[{"award-number":["R01 AR080500"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"award":["R01 AR080500"],"award-info":[{"award-number":["R01 AR080500"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nanomaterials"],"abstract":"<jats:p>Thermoresponsive polymeric prodrugs represent a promising strategy for localized and sustained in vivo drug delivery. In this work, two polyethylene glycol (PEG)-based dexamethasone (Dex) prodrugs with different Dex contents were synthesized using a four-arm PEG scaffold. Prodrug 1, containing four Dex molecules, showed high aqueous solubility but no thermoresponsive gelation behavior. In contrast, eight-Dex Prodrug 2 exhibited temperature-dependent aggregation and formed hydrogels in aqueous media. The viscosity of the Prodrug 2 hydrogel was reduced by introducing 10% ethanol as a cosolvent, enabling an injectable formulation that rapidly forms a hydrogel depot upon contact with aqueous media. The hydrogel provides gradual Dex release via the cleavage of the acid-labile hydrazone bond linking Dex to the PEG. In a monosodium iodoacetate (MIA)-induced osteoarthritis (OA) pain model, intra-articular (IA) injection of Prodrug 2 produced rapid and sustained pain relief for up to 28 days. These findings indicate that the hydrogel-forming four-arm PEG-based Dex prodrug offers a potentially effective approach for prolonged local corticosteroid (CS) delivery, applicable to the treatment of many local pathologies, including OA and OA pain.<\/jats:p>","DOI":"10.3390\/nano16140893","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T16:16:39Z","timestamp":1784650599000},"page":"893","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Development of Four-Arm PEG-Based Thermoresponsive Dexamethasone Prodrugs for the Treatment of Osteoarthritis Pain"],"prefix":"10.3390","volume":"16","author":[{"given":"Yangwei","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3302-3594","authenticated-orcid":false,"given":"Shabnam","family":"Arash","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2794-2666","authenticated-orcid":false,"given":"Jie","family":"Rong","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma Abdullah","family":"Althobaiti","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6240-6027","authenticated-orcid":false,"given":"Eleanor","family":"Ransdell-Green","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1753-9005","authenticated-orcid":false,"given":"Edward V.","family":"Fehringer","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery and Rehabilitation, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-6125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8340-2763","authenticated-orcid":false,"given":"Dong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6125, USA"},{"name":"Department of Orthopaedic Surgery and Rehabilitation, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198-6125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.cger.2010.03.001","article-title":"Epidemiology of osteoarthritis","volume":"26","author":"Zhang","year":"2010","journal-title":"Clin. Geriatr. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1016\/j.joca.2021.06.015","article-title":"A lifespan approach to osteoarthritis prevention","volume":"29","author":"Whittaker","year":"2021","journal-title":"Osteoarthr. Cartil."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41572-025-00594-6","article-title":"Osteoarthritis","volume":"11","author":"Tang","year":"2025","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.jare.2025.01.053","article-title":"Advances in the pathology and treatment of osteoarthritis","volume":"78","author":"Peng","year":"2025","journal-title":"J. Adv. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.clicom.2026.01.003","article-title":"Senescence associated osteoarthritis: Emerging therapeutics and future directions","volume":"9","author":"Razdan","year":"2026","journal-title":"Clin. Immunol. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/s41392-025-02556-6","article-title":"Osteoarthritis: Molecular pathogenesis and potential therapeutic options","volume":"11","author":"Zhang","year":"2026","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_7","unstructured":"Goldenberg, D. (2026, July 16). Evolving Management Strategies for Osteoarthritic Pain. Pract. Pain Manag. 2019, 19. Available online: https:\/\/www.medcentral.com\/rheumatology\/osteoarthritis\/evolving-management-strategies-osteoarthritic-pain."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/s41584-018-0123-4","article-title":"Intra-articular treatment options for knee osteoarthritis","volume":"15","author":"Jones","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"100163","DOI":"10.1016\/j.ostima.2023.100163","article-title":"Debate: Intra-articular steroid injections for osteoarthritis\u2014Harmful or helpful?","volume":"3","author":"Guermazi","year":"2023","journal-title":"Osteoarthr. Imaging"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Hawley, S., Prats-Uribe, A., Matharu, G.S., Delmestri, A., Prieto-Alhambra, D., Judge, A., and Whitehouse, M.R. (2025). Effect of intra-articular corticosteroid injections for knee osteoarthritis on the rates of subsequent knee replacement and post-operative outcomes: A national cohort study of England. BMC Med., 23.","DOI":"10.1186\/s12916-025-04000-6"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1002\/pmrj.12042","article-title":"Systemic Absorption and Side Effects of Locally Injected Glucocorticoids","volume":"11","author":"Stout","year":"2019","journal-title":"PM&R"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1210\/endrev\/bnad016","article-title":"Treating the Side Effects of Exogenous Glucocorticoids; Can We Separate the Good from the Bad?","volume":"44","author":"Pofi","year":"2023","journal-title":"Endocr. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"G25","DOI":"10.1093\/ejendo\/lvae029","article-title":"European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and therapy of glucocorticoid-induced adrenal insufficiency","volume":"190","author":"Beuschlein","year":"2024","journal-title":"Eur. J. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.joca.2017.10.003","article-title":"Synovial and systemic pharmacokinetics (PK) of triamcinolone acetonide (TA) following intra-articular (IA) injection of an extended-release microsphere-based formulation (FX006) or standard crystalline suspension in patients with knee osteoarthritis (OA)","volume":"26","author":"Kraus","year":"2018","journal-title":"Osteoarthr. Cartil."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"(2026, April 26). Pacira BioSciences Reports Fourth Quarter and Full-Year 2025 Financial Results. Available online: https:\/\/investor.pacira.com\/news-releases\/news-release-details\/pacira-biosciences-reports-fourth-quarter-and-full-year-2025.","DOI":"10.1016\/j.fopow.2025.03.013"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S125","DOI":"10.1016\/j.joca.2025.02.171","article-title":"Extended and Controlled Release Liposomal Formulated Dexamethasone (TLC599) for Chronic Knee Osteoarthritis Pain (EXCELLENCE): A Phase 3, Randomized, Placebo-controlled Clinical Trial","volume":"33","author":"Zhu","year":"2025","journal-title":"Osteoarthr. Cartil."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2301394","DOI":"10.1002\/adhm.202301394","article-title":"Reactive Oxygen Species-Responsive Polymeric Prodrug Nanoparticles for Selective and Effective Treatment of Inflammatory Diseases","volume":"12","author":"Zhang","year":"2023","journal-title":"Adv. Healthc. Mater."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e21544","DOI":"10.1016\/j.heliyon.2023.e21544","article-title":"Polymeric biomaterials: Advanced drug delivery systems in osteoarthritis treatment","volume":"9","author":"Liu","year":"2023","journal-title":"Heliyon"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e2409729122","DOI":"10.1073\/pnas.2409729122","article-title":"A mechanically resilient soft hydrogel improves drug delivery for treating post-traumatic osteoarthritis in physically active joints","volume":"122","author":"Joshi","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3874","DOI":"10.1039\/D1TB00499A","article-title":"Thermosensitive polymer hydrogel as a physical shield on colonic mucosa for colitis treatment","volume":"9","author":"Guo","year":"2021","journal-title":"J. Mater. Chem. B"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"137893","DOI":"10.1016\/j.ijbiomac.2024.137893","article-title":"Hydrogel design and applications for periodontitis therapy: A review","volume":"284","author":"Pan","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"123568","DOI":"10.1016\/j.biomaterials.2025.123568","article-title":"Chrono-controlled hydrogel platform orchestrates metabolic reprogramming and cuproptosis-driven immune activation against triple-negative breast cancer","volume":"325","author":"Lu","year":"2026","journal-title":"Biomaterials"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1021\/acs.molpharmaceut.3c01133","article-title":"Thermoresponsive Polymeric Hydromorphone Prodrug Provides Sustained Local Analgesia without Apparent Adverse Effects","volume":"21","author":"Jia","year":"2024","journal-title":"Mol. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5631","DOI":"10.1021\/acs.molpharmaceut.3c00508","article-title":"The Development of Thermoresponsive Polymeric Simvastatin Prodrug for the Treatment of Experimental Periodontitis in Rats","volume":"20","author":"Xu","year":"2023","journal-title":"Mol. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.jconrel.2021.10.007","article-title":"Thermoresponsive polymeric dexamethasone prodrug for arthritis pain","volume":"339","author":"Zhao","year":"2021","journal-title":"J. Control. Release"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wei, X., Zhao, G., and Wang, D. (2024). Macromolecular Therapeutics: Development and Delivery Engineering. Neuroimmune Pharmacology and Therapeutics, Springer.","DOI":"10.1007\/978-3-031-68237-7_54"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.jconrel.2020.05.028","article-title":"Structural optimization of HPMA copolymer-based dexamethasone prodrug for improved treatment of inflammatory arthritis","volume":"324","author":"Jia","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"102735","DOI":"10.1016\/j.nano.2024.102735","article-title":"Single dose thermoresponsive dexamethasone prodrug completely mitigates joint pain for 15 weeks in a murine model of osteoarthritis","volume":"57","author":"Chen","year":"2024","journal-title":"Nanomed. NBM"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"102782","DOI":"10.1016\/j.nano.2024.102782","article-title":"Identification of formulation parameters that affect the analgesic efficacy of ProGel-Dex\u2014A thermoresponsive polymeric dexamethasone prodrug for chronic arthritis pain relief","volume":"62","author":"Wei","year":"2024","journal-title":"Nanomed. NBM"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"102885","DOI":"10.1016\/j.nano.2025.102885","article-title":"Pharmacokinetic and biodistribution (PK\/BD) study of ProGel-Dex, a thermoresponsive dexamethasone prodrug for sustained joint pain relief in a mouse model of osteoarthritis","volume":"71","author":"Wei","year":"2026","journal-title":"Nanomed. NBM"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7663","DOI":"10.1021\/acsnano.8b01249","article-title":"Micelle-Forming Dexamethasone Prodrug Attenuates Nephritis in Lupus-Prone Mice without Apparent Glucocorticoid Side Effects","volume":"12","author":"Jia","year":"2018","journal-title":"ACS Nano"},{"key":"ref_32","first-page":"56","article-title":"A polymeric dexamethasone prodrug attenuates focal segmental glomerulosclerosis (FSGS) in an Adriamycin-induced mouse model with minimal glucocorticoid side effects","volume":"6","author":"Jiang","year":"2025","journal-title":"Smart Mater. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1016\/j.cclet.2019.12.026","article-title":"Synthesis and self-assembly of poly(ethylene glycol)-block-poly(N-3-(methylthio)propyl glycine) and their oxidation-sensitive polymersomes","volume":"31","author":"Deng","year":"2020","journal-title":"Chin. Chem. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1002\/marc.200800713","article-title":"Self-Assembled Block Copolymer Aggregates: From Micelles to Vesicles and their Biological Applications","volume":"30","author":"Blanazs","year":"2009","journal-title":"Macromol. Rapid Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"15520","DOI":"10.1038\/srep15520","article-title":"New aspects in the phase behaviour of poly-N-isopropyl acrylamide: Systematic temperature dependent shrinking of PNiPAM assemblies well beyond the LCST","volume":"5","author":"Bischofberger","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3435","DOI":"10.1021\/acs.biomac.9b00713","article-title":"Oxidation-Sensitive Polymersomes Based on Amphiphilic Diblock Copolypeptoids","volume":"20","author":"Deng","year":"2019","journal-title":"Biomacromolecules"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1039\/D3LP00114H","article-title":"Thermoresponsive polymers with LCST transition: Synthesis, characterization, and their impact on biomedical frontiers","volume":"1","author":"Yuan","year":"2023","journal-title":"RSC Appl. Polym."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1021\/acs.macromol.1c02324","article-title":"Controlled LCST Behavior and Structure Formation of Alternating Amphiphilic Copolymers in Water","volume":"55","author":"Kostyurina","year":"2022","journal-title":"Macromolecules"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1038\/s41428-023-00811-7","article-title":"Study of the temperature\/HCO3- response mechanism of hyperbranched poly(bis-acrylamide)s","volume":"55","author":"Zhou","year":"2023","journal-title":"Polym. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1007\/s00396-012-2866-9","article-title":"Elucidation of the structure of poly(\u03b3-benzyl-l-glutamate) nanofibers and gel networks in a helicogenic solvent","volume":"291","author":"Niehoff","year":"2013","journal-title":"Colloid Polym. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2417544","DOI":"10.1002\/adfm.202417544","article-title":"Thermally Induced Gelling Systems Based on Patchy Polymeric Micelles","volume":"35","author":"Han","year":"2025","journal-title":"Adv. Funct. Mater."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8293","DOI":"10.1021\/ma970884f","article-title":"Hydrophobic Interactions of Poly(N-isopropylacrylamide) with Hydrophobically Modified Poly(sodium acrylate) in Aqueous Solution","volume":"30","author":"Bokias","year":"1997","journal-title":"Macromolecules"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"122733","DOI":"10.1016\/j.polymer.2020.122733","article-title":"Effect of ethanol treatment on physical property of photopolymerized hyaluronic acid\/silk fibroin hybrid hydrogel","volume":"202","author":"Ryoo","year":"2020","journal-title":"Polymer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2309760","DOI":"10.1002\/advs.202309760","article-title":"A Solvent Exchange Induced Robust Wet Adhesive Hydrogels to Treat Solid Tumor Through Synchronous Ethanol Ablation and Chemotherapy","volume":"11","author":"Chen","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4483","DOI":"10.1039\/D4BM00598H","article-title":"Development of injectable colloidal solution forming an in situ hydrogel for tumor ablation","volume":"12","author":"Choi","year":"2024","journal-title":"Biomater. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Vigata, M., Meinert, C., Hutmacher, D.W., and Bock, N. (2020). Hydrogels as Drug Delivery Systems: A Review of Current Characterization and Evaluation Techniques. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12121188"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.jddst.2018.11.012","article-title":"Simulated synovial fluids for in vitro drug and prodrug release testing of depot injectables intended for joint injection","volume":"49","author":"Thing","year":"2019","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"126738","DOI":"10.1016\/j.ijpharm.2026.126738","article-title":"A dynamic device to simulate intraarticular drug-release kinetics","volume":"695","author":"Asik","year":"2026","journal-title":"Int. J. Pharm."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6920","DOI":"10.1021\/acs.molpharmaceut.5c00872","article-title":"Intravitreal Sustained Release of Dexamethasone from a Self-Healing Injectable Hydrogel: An In Vivo Safety and Release Study","volume":"22","author":"Annala","year":"2025","journal-title":"Mol. Pharm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.actbio.2024.10.026","article-title":"Enzyme-responsive microgel with controlled drug release, lubrication and adhesion capability for osteoarthritis attenuation","volume":"190","author":"Chen","year":"2024","journal-title":"Acta Biomater."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1038\/s41467-018-03691-1","article-title":"Towards an arthritis flare-responsive drug delivery system","volume":"9","author":"Joshi","year":"2018","journal-title":"Nat. Commun."}],"container-title":["Nanomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-4991\/16\/14\/893\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T04:20:00Z","timestamp":1784780400000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-4991\/16\/14\/893"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,21]]},"references-count":51,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["nano16140893"],"URL":"https:\/\/doi.org\/10.3390\/nano16140893","relation":{},"ISSN":["2079-4991"],"issn-type":[{"value":"2079-4991","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,21]]}}}