{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T22:19:52Z","timestamp":1787177992378,"version":"build-2736575974"},"reference-count":122,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2015,8,31]],"date-time":"2015-08-31T00:00:00Z","timestamp":1440979200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Biological proteins have unlimited potential for use as pharmaceutical products due to their various biological activities, which include non-toxicity, biocompatibility, and biodegradability. Recent scientific advances allow for the development of novel innovative protein-based products that draw on the quality of their innate biological activities. Some of them hold promising potential for novel therapeutic agents\/devices for addressing hepatic diseases such as hepatitis, fibrosis, and hepatocarcinomas. This review attempts to provide an overview of the development of protein-based products that take advantage of their biological activity for medication, and discusses possibilities for the therapeutic potential of protein-based products produced through different approaches to specifically target the liver (or hepatic cells: hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells, and Kupffer cells) in the treatment of hepatic diseases.<\/jats:p>","DOI":"10.3390\/pharmaceutics7030255","type":"journal-article","created":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T10:55:58Z","timestamp":1441104958000},"page":"255-274","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Potential Use of Biological Proteins for Liver Failure Therapy"],"prefix":"10.3390","volume":"7","author":[{"given":"Kazuaki","family":"Taguchi","sequence":"first","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 862-0082, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keishi","family":"Yamasaki","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 862-0082, Japan"},{"name":"DDS Research Institute, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 862-0082, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hakaru","family":"Seo","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 862-0082, Japan"},{"name":"DDS Research Institute, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 862-0082, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Otagiri","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 862-0082, Japan"},{"name":"DDS Research Institute, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 862-0082, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.jconrel.2014.05.036","article-title":"State-of-the-art in design rules for drug delivery platforms: Lessons learned from FDA-approved nanomedicines","volume":"187","author":"Dawidczyk","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_2","first-page":"99","article-title":"Albumin-bound formulation of paclitaxel (Abraxane\u00ae ABI-007) in the treatment of breast cancer","volume":"4","author":"Miele","year":"2009","journal-title":"Int. J. Nanomed."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1111\/j.1478-3231.2006.01342.x","article-title":"Role of Kupffer cells in host defense and liver disease","volume":"26","author":"Bilzer","year":"2006","journal-title":"Liver Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1002\/jps.22286","article-title":"Alteration in the pharmacokinetics of hemoglobin-vesicles in a rat model of chronic liver cirrhosis is associated with Kupffer cell phagocyte activity","volume":"100","author":"Taguchi","year":"2011","journal-title":"J. Pharm. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1038\/ncomms3823","article-title":"Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology","volume":"4","author":"Mederacke","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.jconrel.2012.02.011","article-title":"Drug targeting to the diseased liver","volume":"161","author":"Poelstra","year":"2012","journal-title":"J. Control. Release"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"382184","DOI":"10.1155\/2013\/382184","article-title":"Efficient hepatic delivery of drugs: Novel strategies and their significance","volume":"2013","author":"Mishra","year":"2013","journal-title":"Biomed. Res. Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.ejim.2013.05.015","article-title":"Clinical indications for the albumin use: Still a controversial issue","volume":"24","author":"Caraceni","year":"2013","journal-title":"Eur. J. Int. Med."},{"key":"ref_9","unstructured":"Otagiri, M., Chuang, V.T., Maruyama, T., and Kragh-Hansen, U. (2013). Human Serum Albumin, Sojo University Publishing Center."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jconrel.2010.03.010","article-title":"Genetically engineered mannosylated-human serum albumin as a versatile carrier for liver-selective therapeutics","volume":"145","author":"Hirata","year":"2010","journal-title":"J. Control. Release"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1124\/jpet.114.219493","article-title":"Polythiol-containing, recombinant mannosylated-albumin is a superior CD68+\/CD206+ Kupffer cell-targeted nano-antioxidant for treatment of two acute hepatitis models","volume":"352","author":"Maeda","year":"2015","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/j.jhep.2010.04.037","article-title":"Characterization of two F4\/80-positive Kupffer cell subsets by their function and phenotype in mice","volume":"53","author":"Kinoshita","year":"2010","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1586\/egh.11.92","article-title":"Update on hepatic stellate cells: Pathogenic role in liver fibrosis and novel isolation techniques","volume":"6","author":"Tacke","year":"2012","journal-title":"Expert. Rev. Gastroenterol. Hepatol."},{"key":"ref_14","first-page":"1429","article-title":"Insulinlike growth factor-II\/mannose 6-phosphate receptor is expressed on CCl4-exposed rat fat-storing cells and facilitates activation of latent transforming growth factor-beta in cocultures with sinusoidal endothelial cells","volume":"21","author":"Jannes","year":"1995","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e56442","DOI":"10.1371\/journal.pone.0056442","article-title":"Enhanced effectivity of an ALK5-inhibitor after cell-specific delivery to hepatic stellate cells in mice with liver injury","volume":"8","author":"Prakash","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1016\/j.jhep.2012.07.033","article-title":"HSC-specific inhibition of Rho-kinase reduces portal pressure in cirrhotic rats without major systemic effects","volume":"57","author":"Klein","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1111\/j.1478-3231.2007.01452.x","article-title":"Hepatic stellate cell-targeted delivery of M6P-HSA-glycyrrhetinic acid attenuates hepatic fibrogenesis in a bile duct ligation rat model","volume":"27","author":"Luk","year":"2007","journal-title":"Liver Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1016\/j.bcp.2006.12.017","article-title":"Pharmacokinetics of a hepatic stellate cell-targeted doxorubicin construct in bile duct-ligated rats","volume":"73","author":"Greupink","year":"2007","journal-title":"Biochem. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1021\/bc500536y","article-title":"Parallel multifunctionalization of nanoparticles: A one-step modular approach for in vivo imaging","volume":"26","author":"Groult","year":"2015","journal-title":"Bioconjug. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.jconrel.2011.07.031","article-title":"Albumin-based nanoparticles as potential controlled release drug delivery systems","volume":"157","author":"Elzoghby","year":"2012","journal-title":"J. Control. Release"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.ijpharm.2007.08.001","article-title":"Preparation and characterization of sodium ferulate entrapped bovine serum albumin nanoparticles for liver targeting","volume":"349","author":"Li","year":"2008","journal-title":"Int. J. Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1211\/jpp.61.09.0004","article-title":"Mannose 6-phosphate-modified bovine serum albumin nanoparticles for controlled and targeted delivery of sodium ferulate for treatment of hepatic fibrosis","volume":"61","author":"Li","year":"2009","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_23","first-page":"111","article-title":"Prednisolone-loaded albumin nanospheres: In vitro and in vivo evaluation studies","volume":"62","author":"Kapoor","year":"2008","journal-title":"PDA J. Pharm. Sci. Technol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1081\/DDC-100102311","article-title":"Study of biodistribution of methotrexate-loaded bovine serum albumin nanospheres in mice","volume":"26","author":"Santhi","year":"2000","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S0168-3659(99)00248-5","article-title":"Tumor vascular permeability and the EPR effect in macromolecular therapeutics: A review","volume":"65","author":"Maeda","year":"2000","journal-title":"J. Control. Release"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1021\/mp500394v","article-title":"Doxorubicin-loaded glycyrrhetinic Acid modified recombinant human serum albumin nanoparticles for targeting liver tumor chemotherapy","volume":"12","author":"Qi","year":"2015","journal-title":"Mol. Pharm."},{"key":"ref_27","first-page":"1207","article-title":"Preparation of 10-hydroxy-camptothecin-loaded glycyrrhizic acid-conjugated bovine serum albumin nanoparticles for hepatocellular carcinoma-targeted drug delivery","volume":"8","author":"Zu","year":"2013","journal-title":"Int. J. Nanomed."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/s11095-011-0603-6","article-title":"Liver cancer targeting of Doxorubicin with reduced distribution to the heart using hemato-porphyrin-modified albumin nanoparticles in rats","volume":"29","author":"Chang","year":"2012","journal-title":"Pharm. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.phrs.2011.06.015","article-title":"A galactosamine-mediated drug delivery carrier for targeted liver cancer therapy","volume":"64","author":"Shen","year":"2011","journal-title":"Pharmacol. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.ejpb.2013.12.010","article-title":"Biodegradable human serum albumin nanoparticles as contrast agents for the detection of hepatocellular carcinoma by magnetic resonance imaging","volume":"87","author":"Watcharin","year":"2014","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.biologicals.2005.08.021","article-title":"Summary of recombinant human serum albumin development","volume":"34","author":"Kobayashi","year":"2006","journal-title":"Biologicals"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1358\/dot.2007.43.8.1067343","article-title":"Recombinant human serum albumin","volume":"43","author":"Chuang","year":"2007","journal-title":"Drugs Today"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1172\/JCI104594","article-title":"Studies of I-131-albumin catabolism and distribution in normal young male adults","volume":"41","author":"Beeken","year":"1962","journal-title":"J. Clin. Investig."},{"key":"ref_34","first-page":"183","article-title":"Studies of the metabolism and distribution of albumin with autologous I131-albumin in healthy men","volume":"61","author":"Takeda","year":"1963","journal-title":"J. Lab. Clin. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jconrel.2010.05.020","article-title":"Albumin fusion of thioredoxin\u2014The production and evaluation of its biological activity for potential therapeutic applications","volume":"147","author":"Ikuta","year":"2010","journal-title":"J. Control. Release"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"514","DOI":"10.3389\/fimmu.2013.00514","article-title":"Thioredoxin\/Txnip: Redoxisome, as a redox switch for the pathogenesis of diseases","volume":"4","author":"Yoshihara","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1053\/jhep.2003.50203","article-title":"Overexpression of thioredoxin prevents acute hepatitis caused by thioacetamide or lipopoly-saccharide in mice","volume":"37","author":"Okuyama","year":"2003","journal-title":"Hepatology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.jhep.2004.09.020","article-title":"Overexpression of thioredoxin prevents thioacetamide-induced hepatic fibrosis in mice","volume":"42","author":"Okuyama","year":"2005","journal-title":"J. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"15143","DOI":"10.1073\/pnas.191498798","article-title":"Circulating thioredoxin suppresses lipopolysaccharide-induced neutrophil chemotaxis","volume":"98","author":"Nakamura","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1021\/mp400690v","article-title":"Albumin fusion prolongs the antioxidant and anti-inflammatory activities of thioredoxin in mice with acetaminophen-induced hepatitis","volume":"11","author":"Tanaka","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.3748\/wjg.v20.i11.2941","article-title":"Medicinal plants against hepatitis C virus","volume":"20","author":"Ashfaq","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1038\/nbt1364","article-title":"Albinterferon alpha-2b: A genetic fusion protein for the treatment of chronic hepatitis C","volume":"25","author":"Subramanian","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1053\/j.gastro.2010.06.062","article-title":"Albinterferon Alfa-2b was not inferior to pegylated interferon-alpha in a randomized trial of patients with chronic hepatitis C virus genotype 2 or 3","volume":"139","author":"Nelson","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1053\/j.gastro.2010.06.066","article-title":"Albinterferon Alfa-2b was not inferior to pegylated interferon-alpha in a randomized trial of patients with chronic hepatitis C virus genotype 1","volume":"139","author":"Zeuzem","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1111\/j.1365-2893.2012.01586.x","article-title":"Randomized trial of albinterferon alfa-2b every 4 weeks for chronic hepatitis C virus genotype 2\/3","volume":"19","author":"Pianko","year":"2012","journal-title":"J. Viral Hepat."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1111\/jgh.12671","article-title":"Randomized, controlled pharmacokinetic and pharmacodynamic evaluation of albinterferon in patients with chronic hepatitis B infection","volume":"30","author":"Colvin","year":"2015","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"58","DOI":"10.2174\/22113525113119990108","article-title":"Population pharmacokinetics and pharmacodynamics of albinterferon alfa-2b in patients treated for hepatitis C virus genotype 2\/3","volume":"12","author":"Yu","year":"2014","journal-title":"Anti-Infect. Agents"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"105","DOI":"10.2174\/138920012798356934","article-title":"PEGylation of proteins and liposomes: A powerful and flexible strategy to improve the drug delivery","volume":"13","author":"Milla","year":"2012","journal-title":"Curr. Drug Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e39111","DOI":"10.1371\/journal.pone.0039111","article-title":"PEG-albumin plasma expansion increases expression of MCP-1 evidencing increased circulatory wall shear stress: An experimental study","volume":"7","author":"Hightower","year":"2012","journal-title":"PLoS ONE"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4477","DOI":"10.1016\/j.biomaterials.2006.04.008","article-title":"PEGylated albumin-heme as an oxygen-carrying plasma expander: Exchange transfusion into acute anemia rat model","volume":"27","author":"Huang","year":"2006","journal-title":"Biomaterials"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1002\/btpr.1526","article-title":"PEGylation of bovine serum albumin using click chemistry for the application as drug carriers","volume":"28","author":"Li","year":"2012","journal-title":"Biotechnol. Prog."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.1002\/jbm.a.35430","article-title":"Scaffold materials from glycosylated and PEGylated bovine serum albumin","volume":"103","author":"Wang","year":"2015","journal-title":"J. Biomed. Mater. Res. A."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.ejpb.2011.05.003","article-title":"Effects of PEG size on structure, function and stability of PEGylated BSA","volume":"79","author":"Plesner","year":"2011","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.ijpharm.2008.08.037","article-title":"Effect of polyols on polyethylene glycol (PEG)-induced precipitation of proteins: Impact on solubility, stability and conformation","volume":"366","author":"Kumar","year":"2009","journal-title":"Int. J. Pharm."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1124\/jpet.105.087429","article-title":"Development of polyethylene glycol-conjugated poly-S-nitrosated serum albumin, a novel S-Nitrosothiol for prolonged delivery of nitric oxide in the blood circulation in vivo","volume":"314","author":"Katsumi","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1097\/TP.0b013e31815e902b","article-title":"Prevention of hepatic ischemia\/reperfusion injury by prolonged delivery of nitric oxide to the circulating blood in mice","volume":"85","author":"Katsumi","year":"2008","journal-title":"Transplantation"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.freeradbiomed.2014.01.036","article-title":"Development of PEGylated serum albumin with multiple reduced thiols as a long-circulating scavenger of reactive oxygen species for the treatment of fulminant hepatic failure in mice","volume":"69","author":"Katsumi","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1097\/00041552-200111000-00008","article-title":"Albumin dialysis using the molecular adsorbent recirculating system","volume":"10","author":"Mitzner","year":"2001","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/j.cld.2014.07.011","article-title":"Molecular adsorbent recirculating system and bioartificial devices for liver failure","volume":"18","author":"Banares","year":"2014","journal-title":"Clin. Liver Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/aor.12106","article-title":"Extracorporeal detoxification for hepatic failure using molecular adsorbent recirculating system: Depurative efficiency and clinical results in a long-term follow-up","volume":"38","author":"Donati","year":"2014","journal-title":"Artif. Organs"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1002\/hep.26185","article-title":"Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: The RELIEF trial","volume":"57","author":"Banares","year":"2013","journal-title":"Hepatology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2917","DOI":"10.1016\/j.bbagen.2013.01.006","article-title":"Albumin domain II mutant with high bilirubin binding affinity has a great potential as serum bilirubin excretion enhancer for hyperbilirubinemia treatment","volume":"1830","author":"Minomo","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4100","DOI":"10.1111\/j.1742-4658.2011.08316.x","article-title":"Biological characteristics of two lysines on human serum albumin in the high-affinity binding of 4Z,15Z-bilirubin-IXalpha revealed by phage display","volume":"278","author":"Minomo","year":"2011","journal-title":"FEBS J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.bbagen.2011.06.018","article-title":"Lactoferrin a multiple bioactive protein: An overview","volume":"1820","author":"Cendon","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1002\/hep.23476","article-title":"Lactoferrin protects against acetaminophen-induced liver injury in mice","volume":"51","author":"Yin","year":"2010","journal-title":"Hepatology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1111\/j.1478-3231.2009.02199.x","article-title":"Lactoferrin protects against concanavalin A-induced liver injury in mice","volume":"30","author":"Yin","year":"2010","journal-title":"Liver Int."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s00011-003-1178-4","article-title":"Bovine lactoferrin decreases histopathological changes in the liver and regulates cytokine production by splenocytes of obstructive jaundiced rats","volume":"52","author":"Zimecki","year":"2003","journal-title":"Inflamm. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1139\/o11-084","article-title":"Effect of bovine lactoferrin in a therapeutic hamster model of hepatic amoebiasis","volume":"90","year":"2012","journal-title":"Biochem. Cell Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1017\/S0007114513004315","article-title":"Bovine lactoferrin ingestion protects against inflammation via IL-11 induction in the small intestine of mice with hepatitis","volume":"111","author":"Kuhara","year":"2014","journal-title":"Br. J. Nutr."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3281","DOI":"10.3168\/jds.2013-7505","article-title":"Lactoferrin protects against chemical-induced rat liver fibrosis by inhibiting stellate cell activation","volume":"97","author":"Tung","year":"2014","journal-title":"J. Dairy Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S0168-1702(99)00121-5","article-title":"Characterization of antiviral activity of lactoferrin against hepatitis C virus infection in human cultured cells","volume":"66","author":"Ikeda","year":"2000","journal-title":"Virus Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1006\/bbrc.1998.8481","article-title":"Lactoferrin markedly inhibits hepatitis C virus infection in cultured human hepatocytes","volume":"245","author":"Ikeda","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1007\/s11095-009-9925-z","article-title":"Lactoferrin conjugated with 40-kDa branched poly(ethylene glycol) has an improved circulating half-life","volume":"26","author":"Nojima","year":"2009","journal-title":"Pharm. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1292\/jvms.09-0324","article-title":"PEGylated lactoferrin enhances its hepatoprotective effects on acute liver injury induced by d-galactosamine and lipopolysaccharide in rats","volume":"72","author":"Sugiyama","year":"2010","journal-title":"J. Vet. Med. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/j.fct.2009.03.030","article-title":"PEGylated lactoferrin enhanced its hepatoprotective effects on acute liver injury induced by carbon tetrachloride in rats","volume":"47","author":"Sugiyama","year":"2009","journal-title":"Food Chem. Toxicol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.ejps.2014.11.005","article-title":"Recombinant human lactoferrin-Fc fusion with an improved plasma half-life","volume":"67","author":"Shiga","year":"2015","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/978-1-4757-9068-9_14","article-title":"Identification and analysis of a CA(2+)-dependent lactoferrin receptor in rat liver. Lactoferrin binds to the asialoglycoprotein receptor in a galactose-independent manner","volume":"443","author":"McAbee","year":"1998","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1080\/10611860701502889","article-title":"Targeting of stabilized plasmid lipid particles to hepatocytes in vivo by means of coupled lactoferrin","volume":"15","author":"Bartsch","year":"2007","journal-title":"J. Drug Target."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.ejps.2012.02.007","article-title":"Hepatocellular carcinoma targeting effect of PEGylated liposomes modified with lactoferrin","volume":"46","author":"Wei","year":"2012","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.ijbiomac.2014.07.041","article-title":"Carboplatin loaded protein nanoparticles exhibit improve anti-proliferative activity in retinoblastoma cells","volume":"70","author":"Ahmed","year":"2014","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"644","DOI":"10.7150\/jca.7093","article-title":"A target-specific oral formulation of Doxorubicin-protein nanoparticles: Efficacy and safety in hepatocellular cancer","volume":"4","author":"Golla","year":"2013","journal-title":"J. Cancer"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e51960","DOI":"10.1371\/journal.pone.0051960","article-title":"Efficacy, safety and anticancer activity of protein nanoparticle-based delivery of doxorubicin through intravenous administration in rats","volume":"7","author":"Golla","year":"2012","journal-title":"PLoS ONE"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3116","DOI":"10.1016\/S0021-9258(17)35756-3","article-title":"Structural characterization of human erythropoietin","volume":"261","author":"Lai","year":"1986","journal-title":"J. Biol. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.jss.2013.01.044","article-title":"Recombinant human erythropoietin preconditioning attenuates liver ischemia reperfusion injury through the phosphatidylinositol-3 kinase\/AKT\/endothelial nitric oxide synthase pathway","volume":"183","author":"Fu","year":"2013","journal-title":"J. Surg. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1097\/SHK.0000000000000231","article-title":"Hepatocellular heme oxygenase-1: A potential mechanism of erythropoietin-mediated protection after liver ischemia-reperfusion injury","volume":"42","author":"Riehle","year":"2014","journal-title":"Shock"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s13105-011-0114-2","article-title":"Effect of recombinant erythropoietin on ischemia-reperfusion-induced apoptosis in rat liver","volume":"68","author":"Shawky","year":"2012","journal-title":"J. Physiol. Biochem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.injury.2009.12.006","article-title":"Erythropoietin protects severe haemorrhagic shock-induced organ damage in conscious rats","volume":"41","author":"Wu","year":"2010","journal-title":"Injury"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1007\/s12325-008-0114-y","article-title":"The role of erythropoietin in hemorrhagic shock-induced liver and renal injury in rats","volume":"25","author":"Algin","year":"2008","journal-title":"Adv. Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1097\/TP.0b013e31821cdea5","article-title":"Erythropoietin increases survival and attenuates fulminant hepatic failure injury induced by d-galactosamine\/lipopolysaccharide in mice","volume":"92","author":"Zilbermints","year":"2011","journal-title":"Transplantation"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"555","DOI":"10.3892\/mmr.2014.2164","article-title":"Hepatoprotective effects of erythropoietin on d-galactosamine\/lipopolysaccharide-induced fulminant hepatic failure in mice","volume":"10","author":"Yang","year":"2014","journal-title":"Mol. Med. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1111\/j.1440-1746.2007.05265.x","article-title":"Erythropoietin promotes hepatic regeneration after extended liver resection in rats","volume":"23","author":"Schmeding","year":"2008","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/lt.22046","article-title":"Dual effect of erythropoietin on liver protection and regeneration after subtotal hepatectomy in rats","volume":"16","author":"Greif","year":"2010","journal-title":"Liver Transpl."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.ijsu.2012.11.012","article-title":"Effect of erythropoietin on liver regeneration in an experimental model of partial hepatectomy","volume":"11","author":"Gul","year":"2013","journal-title":"Int. J. Surg."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.3748\/wjg.v19.i7.1104","article-title":"Granulocyte-colony stimulating factor therapy improves survival in patients with hepatitis B virus-associated acute-on-chronic liver failure","volume":"19","author":"Duan","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1053\/j.gastro.2011.11.027","article-title":"Granulocyte colony-stimulating factor mobilizes CD34(+) cells and improves survival of patients with acute-on-chronic liver failure","volume":"142","author":"Garg","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/1477-7819-8-57","article-title":"The combined effect of erythropoietin and granulocyte macrophage colony stimulating factor on liver regeneration after major hepatectomy in rats","volume":"8","author":"Vassiliou","year":"2010","journal-title":"World J. Surg. Oncol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1053\/j.gastro.2015.02.054","article-title":"Combination of Granulocyte Colony-Stimulating Factor and Erythropoietin Improves Outcomes of Patients with Decompensated Cirrhosis","volume":"148","author":"Kedarisetty","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S0167-4838(00)00153-9","article-title":"Alpha-1-acid glycoprotein","volume":"1482","author":"Fournier","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1263\/jbb.99.81","article-title":"Suppression of cell death in primary rat hepatocytes by alpha1-acid glycoprotein","volume":"99","author":"Kagaya","year":"2005","journal-title":"J. Biosci. Bioeng."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"5235","DOI":"10.4049\/jimmunol.163.10.5235","article-title":"Activation of caspases in lethal experimental hepatitis and prevention by acute phase proteins","volume":"163","author":"Denecker","year":"1999","journal-title":"J. Immunol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"3555","DOI":"10.4049\/jimmunol.159.7.3555","article-title":"Alpha 1-acid glycoprotein and alpha 1-antitrypsin inhibit TNF-induced but not anti-Fas-induced apoptosis of hepatocytes in mice","volume":"159","author":"Libert","year":"1997","journal-title":"J. Immunol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.ejphar.2006.05.003","article-title":"Protective effects of alpha1-acid glycoprotein and serum amyloid A on concanavalin A-induced liver failure via interleukin-6 induction by ME3738","volume":"541","author":"Kuzuhara","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/j.jconrel.2013.09.019","article-title":"Gelatin-based nanoparticles as drug and gene delivery systems: Reviewing three decades of research","volume":"172","author":"Elzoghby","year":"2013","journal-title":"J. Control. Release"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1136\/gut.2008.165647","article-title":"A novel technique for selective NF-kappaB inhibition in Kupffer cells: Contrary effects in fulminant hepatitis and ischaemia-reperfusion","volume":"58","author":"Hoffmann","year":"2009","journal-title":"Gut"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"883","DOI":"10.3109\/1061186X.2012.725169","article-title":"Exploiting 4-sulphate N-acetyl galactosamine decorated gelatin nanoparticles for effective targeting to professional phagocytes in vitro and in vivo","volume":"20","author":"Dwivedi","year":"2012","journal-title":"J. Drug Target."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.nano.2007.11.004","article-title":"Mannosylated gelatin nanoparticles bearing an anti-HIV drug didanosine for site-specific delivery","volume":"4","author":"Jain","year":"2008","journal-title":"Nanomedicine"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1097\/CAD.0b013e328351424f","article-title":"Galactosylated gelatin nanovectors of doxorubicin inhibit cell proliferation and induce apoptosis in hepatocarcinoma cells","volume":"23","author":"Garg","year":"2012","journal-title":"Anticancer Drugs"},{"key":"ref_108","first-page":"1009","article-title":"Hemospan: A hemoglobin-based oxygen carrier for potential use as a blood substitute and for the potential treatment of critical limb ischemia","volume":"9","author":"Smani","year":"2008","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1590\/S1807-59322009000800016","article-title":"A review of blood substitutes: Examining the history, clinical trial results, and ethics of hemoglobin-based oxygen carriers","volume":"64","author":"Chen","year":"2009","journal-title":"Clinics"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1517\/14712598.8.9.1425","article-title":"HBOC-201, hemoglobin glutamer-250 (bovine), Hemopure (Biopure Corporation)","volume":"8","author":"Jahr","year":"2008","journal-title":"Expert. Opin. Biol. Ther."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"188","DOI":"10.2174\/157016312802650805","article-title":"Present situation of the development of cellular-type hemoglobin-based oxygen carrier (hemoglobin-vesicles)","volume":"9","author":"Sakai","year":"2012","journal-title":"Curr. Drug Discov. Technol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"428","DOI":"10.3109\/21691401.2012.762370","article-title":"Carbon monoxide form of PEGylated hemoglobin protects myocardium against ischemia\/reperfusion injury in diabetic and normal mice","volume":"41","author":"Ananthakrishnan","year":"2013","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"6553","DOI":"10.1016\/j.biomaterials.2014.04.049","article-title":"Carbon monoxide-bound hemoglobin-vesicles for the treatment of bleomycin-induced pulmonary fibrosis","volume":"35","author":"Nagao","year":"2014","journal-title":"Biomaterials"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1097\/SHK.0b013e318188f83d","article-title":"Hemoglobin vesicles and red blood cells as carriers of carbon monoxide prior to oxygen for resuscitation after hemorrhagic shock in a rat model","volume":"31","author":"Sakai","year":"2009","journal-title":"Shock"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.1002\/jps.24029","article-title":"Carbon monoxide-bound red blood cell resuscitation ameliorates hepatic injury induced by massive hemorrhage and red blood cell resuscitation via hepatic cytochrome P450 protection in hemorrhagic shock rats","volume":"103","author":"Ogaki","year":"2014","journal-title":"J. Pharm. Sci."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1124\/dmd.112.048744","article-title":"Carbon monoxide-bound red blood cells protect red blood cell transfusion-induced hepatic cytochrome P450 impairment in hemorrhagic-shock rats","volume":"41","author":"Ogaki","year":"2013","journal-title":"Drug Metab. Dispos."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/35051594","article-title":"Identification of the haemoglobin scavenger receptor","volume":"409","author":"Kristiansen","year":"2001","journal-title":"Nature"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1182\/blood-2005-03-1014","article-title":"CD163 is the macrophage scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin","volume":"107","author":"Schaer","year":"2006","journal-title":"Blood"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1002\/bit.24340","article-title":"Liposomes surface conjugated with human hemoglobin target delivery to macrophages","volume":"109","author":"Zhang","year":"2012","journal-title":"Biotechnol. Bioeng."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1021\/bc0503317","article-title":"Synthesis and characterization of a hemoglobin-ribavirin conjugate for targeted drug delivery","volume":"17","author":"Brookes","year":"2006","journal-title":"Bioconjug. Chem."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1002\/hep.21072","article-title":"Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity","volume":"43","author":"Levy","year":"2006","journal-title":"Hepatology"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.1089\/ars.2012.4834","article-title":"CD163 and inflammation: Biological, diagnostic, and therapeutic aspects","volume":"18","author":"Etzerodt","year":"2013","journal-title":"Antioxid. Redox Signal."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/7\/3\/255\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:47:46Z","timestamp":1760215666000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/7\/3\/255"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,31]]},"references-count":122,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2015,9]]}},"alternative-id":["pharmaceutics7030255"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics7030255","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,31]]}}}