{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:40:29Z","timestamp":1790048429178,"version":"4.0.1"},"reference-count":46,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2016,12,24]],"date-time":"2016-12-24T00:00:00Z","timestamp":1482537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>In this study, we developed curcumin-encapsulated hyaluronic acid\u2013polylactide nanoparticles (CEHPNPs) to be used for liver fibrosis amelioration. CD44, the hyaluronic acid (HA) receptor, is upregulated on the surface of cancer cells and on activated hepatic stellate cells (aHSCs) rather than normal cells. CEHPNPs could bind to CD44 and be internalized effectively through endocytosis to release curcumin, a poor water-soluble liver protective agent. Thus, CEHPNPs were potentially not only improving drug efficiency, but also targeting aHSCs. HA and polylactide (PLA) were crosslinked by adipic acid dihydrazide (ADH). The synthesis of HA\u2013PLA was monitored by Fourier-transform infrared (FTIR) and Nuclear Magnetic Resonance (NMR). The average particle size was approximately 60\u201370 nm as determined by dynamic light scattering (DLS) and scanning electron microscope (SEM). Zeta potential was around \u221230 mV, which suggested a good stability of the particles. This drug delivery system induced significant aHSC cell death without affecting quiescent HSCs, hepatic epithelial, and parenchymal cells. This system reduced drug dosage without sacrificing therapeutic efficacy. The cytotoxicity IC50 (inhibitory concentration at 50%) value of CEHPNPs was approximately 1\/30 to that of the free drug treated group in vitro. Additionally, the therapeutic effects of CEHPNPs were as effective as the group treated with the same curcumin dose intensity in vivo. CEHPNPs significantly reduced serum aspartate transaminase\/alanine transaminase (ALT\/AST) significantly, and attenuated tissue collagen production and cell proliferation as revealed by liver biopsy. Conclusively, the advantages of superior biosafety and satisfactory therapeutic effect mean that CEHPNPs hold great potential for treating hepatic fibrosis.<\/jats:p>","DOI":"10.3390\/ijerph14010011","type":"journal-article","created":{"date-parts":[[2016,12,28]],"date-time":"2016-12-28T11:22:14Z","timestamp":1482924134000},"page":"11","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Ameliorative Effect of Curcumin-Encapsulated Hyaluronic Acid\u2013PLA Nanoparticles on Thioacetamide-Induced Murine Hepatic Fibrosis"],"prefix":"10.3390","volume":"14","author":[{"given":"Yu-Nong","family":"Chen","sequence":"first","affiliation":[{"name":"Department Applied Chemistry, College of Science and Technology, National Chi Nan University, Nantou, Puli 545, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Lan","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department Medical Education &amp; Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Yuan","family":"Liao","sequence":"additional","affiliation":[{"name":"Department Chemistry, College of Sciences, National Chung Hsing University, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ting","family":"Liu","sequence":"additional","affiliation":[{"name":"Department Applied Chemistry, College of Science and Technology, National Chi Nan University, Nantou, Puli 545, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Hung","family":"Lai","sequence":"additional","affiliation":[{"name":"Department Applied Chemistry, College of Science and Technology, National Chi Nan University, Nantou, Puli 545, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Feng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department Applied Chemistry, College of Science and Technology, National Chi Nan University, Nantou, Puli 545, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai-Huong","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department Applied Chemistry, College of Science and Technology, National Chi Nan University, Nantou, Puli 545, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Hsiang","family":"Su","sequence":"additional","affiliation":[{"name":"Department Applied Chemistry, College of Science and Technology, National Chi Nan University, Nantou, Puli 545, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shang-Ting","family":"Chen","sequence":"additional","affiliation":[{"name":"Department Applied Chemistry, College of Science and Technology, National Chi Nan University, Nantou, Puli 545, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Chen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department Applied Chemistry, College of Science and Technology, National Chi Nan University, Nantou, Puli 545, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2016,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S38","DOI":"10.1016\/S0168-8278(02)00429-4","article-title":"Liver fibrosis\u2014From bench to bedside","volume":"38","author":"Friedman","year":"2003","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1053\/j.gastro.2008.03.003","article-title":"Mechanisms of hepatic fibrogenesis","volume":"134","author":"Friedman","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_3","first-page":"225","article-title":"Activated hepatic stellate cells in liver cirrhosis. A morphologic and morphometrical study","volume":"109","author":"Carpino","year":"2004","journal-title":"Ital. J. Anat. Embryol."},{"key":"ref_4","first-page":"195","article-title":"Mechanisms of hepatic fibrogenesis. Best practice & research","volume":"25","author":"Lee","year":"2011","journal-title":"Clin. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1002\/hep.21564","article-title":"Sinusoidal remodeling and angiogenesis: A new function for the liver-specific pericyte?","volume":"45","author":"Lee","year":"2007","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1016\/j.jhep.2010.07.004","article-title":"Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: New targets for the treatment of portal hypertension?","volume":"53","author":"Thabut","year":"2010","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1172\/JCI41203","article-title":"Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF\/TGF-beta signaling in hepatic stellate cells","volume":"120","author":"Cao","year":"2010","journal-title":"J. Clin. Investing."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"15398","DOI":"10.1074\/jbc.M414048200","article-title":"Role of CD44 in epithelial wound repair: Migration of rat hepatic stellate cells utilizes hyaluronic acid and CD44v6","volume":"280","author":"Kikuchi","year":"2005","journal-title":"J. Boil. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1046\/j.1365-2796.1997.00170.x","article-title":"Hyaluronan: Its nature, distribution, functions and turnover","volume":"242","author":"Fraser","year":"1997","journal-title":"J. Intern. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1096\/fasebj.6.7.1563592","article-title":"Hyaluronan","volume":"6","author":"Laurent","year":"1992","journal-title":"FASEB J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"H41","DOI":"10.1002\/adma.201003963","article-title":"Hyaluronic acid hydrogels for biomedical applications","volume":"23","author":"Burdick","year":"2011","journal-title":"Adv. Mater."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Fang, X.J., Jiang, H., Zhao, X.P., and Jiang, W.M. (2011). The role of a new CD44st in increasing the invasion capability of the human breast cancer cell line MCF-7. BMC Cancer, 11.","DOI":"10.1186\/1471-2407-11-290"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1152\/physrev.00052.2009","article-title":"Hyaluronan as an immune regulator in human diseases","volume":"91","author":"Jiang","year":"2011","journal-title":"Physiol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/B978-0-12-800092-2.00002-2","article-title":"Targeting hyaluronic acid family for cancer chemoprevention and therapy","volume":"123","author":"Lokeshwar","year":"2014","journal-title":"Adv. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1016\/j.biomaterials.2013.01.077","article-title":"Hyaluronic acid based self-assembling nanosystems for CD44 target mediated siRNA delivery to solid tumors","volume":"34","author":"Ganesh","year":"2013","journal-title":"Biomaterials"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/jbm.a.32704","article-title":"The impact of hyaluronic acid oligomer content on physical, mechanical, and biologic properties of divinyl sulfone-crosslinked hyaluronic acid hydrogels","volume":"94","author":"Ibrahim","year":"2010","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_17","first-page":"6055","article-title":"Natural product-based nanomedicine: Recent advances and issues","volume":"10","author":"Watkins","year":"2015","journal-title":"Int. J. Nanomed."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.2217\/nnm.14.164","article-title":"Antipsychotic nanomedicine: A successful platform for clinical use","volume":"9","author":"Muthu","year":"2014","journal-title":"Nanomedicine"},{"key":"ref_19","first-page":"14787","article-title":"Review of natural productswithhepatoprotectiveeffects","volume":"20","author":"Bautista","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1124\/mol.107.039818","article-title":"Curcumin protects the rat liver from CCl4-caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation","volume":"73","author":"Fu","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1111\/jcmm.12286","article-title":"Curcumin attenuates angiogenesis in liver fibrosis and inhibits angiogenic properties of hepatic stellate cells","volume":"18","author":"Zhang","year":"2014","journal-title":"J. Cell. Mol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"G113","DOI":"10.1152\/ajpgi.00200.2006","article-title":"Disruption of transforming growth factor-beta signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-gamma in rat hepatic stellate cells","volume":"292","author":"Zheng","year":"2007","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/labinvest.2008.20","article-title":"Activation of peroxisome proliferator-activated receptor-gamma by curcumin blocks the signaling pathways for PDGF and EGF in hepatic stellate cells","volume":"88","author":"Lin","year":"2008","journal-title":"Lab. Investig. J. Tech. Methods Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/j.bcp.2007.08.016","article-title":"Curcumin as \u201cCurecumin\u201d: From kitchen to clinic","volume":"75","author":"Goel","year":"2008","journal-title":"Biochem. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1093\/nutrit\/nuu064","article-title":"Curcumin and cancer: Barriers to obtaining a health claim","volume":"73","author":"Devassy","year":"2015","journal-title":"Nutr. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.drudis.2011.09.009","article-title":"Curcumin nanoformulations: A future nanomedicine for cancer","volume":"17","author":"Yallapu","year":"2012","journal-title":"Drug Discov. Today"},{"key":"ref_27","first-page":"3394","article-title":"Guided bone regeneration by poly(lactic-co-glycolic acid) grafted hyaluronic acid bi-layer films for periodontal barrier applications","volume":"5","author":"Park","year":"2009","journal-title":"Actabiomaterialia"},{"key":"ref_28","first-page":"589","article-title":"Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay","volume":"48","author":"Alley","year":"1988","journal-title":"Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0142-9612(99)00129-5","article-title":"Attachment of hyaluronic acid to polypropylene, polystyrene, and polytetrafluoroethylene","volume":"21","author":"Mason","year":"2000","journal-title":"Biomaterials"},{"key":"ref_30","first-page":"1925","article-title":"Curcumin induces apoptosis involving bax\/bcl-2 in human hepatoma SMMC-7721 cells","volume":"12","author":"Yu","year":"2011","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1203\/01.pdr.0000238341.12229.d3","article-title":"Relationship between oxidative stress and antioxidant systems in the liver of patients with Wilson disease: Hepatic manifestation in Wilson disease as a consequence of augmented oxidative stress","volume":"60","author":"Nagasaka","year":"2006","journal-title":"Pediatr. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1755-1536-6-19","article-title":"Experimental liver fibrosis research: Update on animal models, legal issues and translational aspects","volume":"6","author":"Liedtke","year":"2013","journal-title":"Fibrogenesis Tissue Repair"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"218","DOI":"10.2174\/138920112798868791","article-title":"Curcumin and liver cancer: A review","volume":"13","author":"Darvesh","year":"2012","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1208\/s12248-015-9811-z","article-title":"Therapeutic applications of curcumin nanoformulations","volume":"17","author":"Yallapu","year":"2015","journal-title":"AAPS J."},{"key":"ref_35","first-page":"358","article-title":"Down-regulation of Notch1 signaling inhibits tumor growth in human hepatocellular carcinoma","volume":"1","author":"Ning","year":"2009","journal-title":"Am. J. Transl. Res."},{"key":"ref_36","first-page":"227","article-title":"Curcumin inhibits telomerase activity in human cancer cell lines","volume":"18","author":"Cui","year":"2006","journal-title":"Int. J. Mol. Med."},{"key":"ref_37","first-page":"127","article-title":"Antiangiogenic activity of curcumin in hepatocellular carcinoma cells implanted nude mice","volume":"33","author":"Yoysungnoen","year":"2005","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1517\/17425247.2014.916686","article-title":"Recent advances in curcumin nanoformulation for cancer therapy","volume":"11","author":"Lee","year":"2014","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"755","DOI":"10.7150\/thno.10804","article-title":"Coating solid lipid nanoparticles with hyaluronic acid enhances antitumor activity against melanoma stem-like cells","volume":"5","author":"Shen","year":"2015","journal-title":"Theranostics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.fct.2016.08.026","article-title":"In vitro and in vivo toxicity evaluation of cationic PDMAEMA-PCL-PDMAEMA micelles as a carrier of curcumin","volume":"97","author":"Tzankova","year":"2016","journal-title":"Food Chem. Toxicol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/1743-8977-7-25","article-title":"Role of surface charge and oxidative stress in cytotoxicity of organic monolayer-coated silicon nanoparticles towards macrophage NR8383 cells","volume":"7","author":"Bhattacharjee","year":"2010","journal-title":"Part. Fibre Toxicol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/S0142-9612(96)00178-0","article-title":"Evaluation of hepatic antioxidant systems after intravenous administration of polymeric nanoparticles","volume":"18","author":"Fattal","year":"1997","journal-title":"Biomaterials"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5669","DOI":"10.1038\/srep05669","article-title":"Tuning pharmacokinetics and biodistribution of a targeted drug delivery system through incorporation of a passive targeting component","volume":"4","author":"Kudgus","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.addr.2008.09.012","article-title":"Micro- and macrorheology of mucus","volume":"61","author":"Lai","year":"2009","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF02980037","article-title":"Control of encapsulation efficiency and initial burst in polymeric microparticle systems","volume":"27","author":"Yeo","year":"2004","journal-title":"Arch. Pharm. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/0169-409X(89)90024-0","article-title":"Generating and loading of liposomal systems for drug-delivery applications","volume":"3","author":"Cullis","year":"1989","journal-title":"Adv. Drug Deliv. Rev."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/14\/1\/11\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:29:15Z","timestamp":1760210955000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/14\/1\/11"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,24]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,1]]}},"alternative-id":["ijerph14010011"],"URL":"https:\/\/doi.org\/10.3390\/ijerph14010011","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12,24]]}}}