Polythiol-containing, recombinant mannosylated-albumin is a superior CD68+/CD206+ Kupffer cell-targeted nanoantioxidant for treatment of two acute hepatitis models.
Since reactive oxygen species (ROS) derived from Kupffer cells (KC), especially CD68(+) KC, play a key role in the induction of hepatic oxidative stress and injuries, we developed a polythiolated- and mannosylated human serum albumin (SH-Man-HSA), which functions as a novel nanoantioxidant for delivering thiol to CD68(+) KC. In vitro electron paramagnetic resonance coupled with pharmacokinetics and immunohistochemical studies showed that SH-Man-HSA possessed powerful radical-scavenging activity and rapidly and selectively delivered thiols to the liver via mannose receptor (CD206) on CD68(+) cells. SH-Man-HSA significantly improved the survival rate of concanavalin-A (Con-A)-treated mice. Moreover, SH-Man-HSA exhibited excellent hepatoprotective functions, not by decreasing tumor necrosis factor or interferon-γ production that is closely associated with Con-A-induced hepatitis, but by suppressing ROS production. Interestingly, the protective effect of SH-Man-HSA was superior to N-acetyl cysteine (NAC). This could be attributed to the difference in the inhibition of hepatic oxidative stress between the two antioxidants depending on their potential for thiol delivery to the liver. Similar results were also observed for acetaminophen (APAP)-induced hepatopathy models. Flow cytometric data further confirmed that an increase in F4/80(+)/ROS(+) cells was dramatically decreased by SH-Man-HSA. The administration of SH-Man-HSA at 4 hours following a Con-A or APAP injection also exhibited a profound hepatoprotective action against these hepatitis models, whereas this was not observed for NAC. It can be concluded therefore that SH-Man-HSA has great potential for use in a rescue therapy for hepatopathy as a nanoantioxidant because of its ability to efficiently and rapidly deliver thiols to CD68(+)/CD206(+) KC.
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences (H.M., K.H., H.W., Y.I., V.T.G.C., T.M.), Center for Clinical Pharmaceutical Sciences, School of Pharmacy (H.W., Y.I., T.M.), and Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences (M.T., Y.S.), Kumamoto University, Kumamoto, Japan; School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia (V.T.G.C.); Faculty of Pharmaceutical Sciences (K.T., M.O.) and DDS Research Institute (M.O.), Sojo University, Kumamoto, Japan; and Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan (A.I., M.K.).
Hitoshi
H
Maeda
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences (H.M., K.H., H.W., Y.I., V.T.G.C., T.M.), Center for Clinical Pharmaceutical Sciences, School of Pharmacy (H.W., Y.I., T.M.), and Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences (M.T., Y.S.), Kumamoto University, Kumamoto, Japan; School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia (V.T.G.C.); Faculty of Pharmaceutical Sciences (K.T., M.O.) and DDS Research Institute (M.O.), Sojo University, Kumamoto, Japan; and Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan (A.I., M.K.).
Kenshiro
K
Hirata
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences (H.M., K.H., H.W., Y.I., V.T.G.C., T.M.), Center for Clinical Pharmaceutical Sciences, School of Pharmacy (H.W., Y.I., T.M.), and Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences (M.T., Y.S.), Kumamoto University, Kumamoto, Japan; School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia (V.T.G.C.); Faculty of Pharmaceutical Sciences (K.T., M.O.) and DDS Research Institute (M.O.), Sojo University, Kumamoto, Japan; and Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan (A.I., M.K.).
Hiroshi
H
Watanabe
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences (H.M., K.H., H.W., Y.I., V.T.G.C., T.M.), Center for Clinical Pharmaceutical Sciences, School of Pharmacy (H.W., Y.I., T.M.), and Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences (M.T., Y.S.), Kumamoto University, Kumamoto, Japan; School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia (V.T.G.C.); Faculty of Pharmaceutical Sciences (K.T., M.O.) and DDS Research Institute (M.O.), Sojo University, Kumamoto, Japan; and Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan (A.I., M.K.).
Yu
Y
Ishima
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences (H.M., K.H., H.W., Y.I., V.T.G.C., T.M.), Center for Clinical Pharmaceutical Sciences, School of Pharmacy (H.W., Y.I., T.M.), and Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences (M.T., Y.S.), Kumamoto University, Kumamoto, Japan; School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia (V.T.G.C.); Faculty of Pharmaceutical Sciences (K.T., M.O.) and DDS Research Institute (M.O.), Sojo University, Kumamoto, Japan; and Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan (A.I., M.K.).
Victor Tuan Giam
VT
Chuang
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences (H.M., K.H., H.W., Y.I., V.T.G.C., T.M.), Center for Clinical Pharmaceutical Sciences, School of Pharmacy (H.W., Y.I., T.M.), and Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences (M.T., Y.S.), Kumamoto University, Kumamoto, Japan; School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia (V.T.G.C.); Faculty of Pharmaceutical Sciences (K.T., M.O.) and DDS Research Institute (M.O.), Sojo University, Kumamoto, Japan; and Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan (A.I., M.K.).
Kazuaki
K
Taguchi
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences (H.M., K.H., H.W., Y.I., V.T.G.C., T.M.), Center for Clinical Pharmaceutical Sciences, School of Pharmacy (H.W., Y.I., T.M.), and Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences (M.T., Y.S.), Kumamoto University, Kumamoto, Japan; School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia (V.T.G.C.); Faculty of Pharmaceutical Sciences (K.T., M.O.) and DDS Research Institute (M.O.), Sojo University, Kumamoto, Japan; and Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan (A.I., M.K.).
Akihito
A
Inatsu
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences (H.M., K.H., H.W., Y.I., V.T.G.C., T.M.), Center for Clinical Pharmaceutical Sciences, School of Pharmacy (H.W., Y.I., T.M.), and Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences (M.T., Y.S.), Kumamoto University, Kumamoto, Japan; School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia (V.T.G.C.); Faculty of Pharmaceutical Sciences (K.T., M.O.) and DDS Research Institute (M.O.), Sojo University, Kumamoto, Japan; and Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan (A.I., M.K.).
Manabu
M
Kinoshita
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences (H.M., K.H., H.W., Y.I., V.T.G.C., T.M.), Center for Clinical Pharmaceutical Sciences, School of Pharmacy (H.W., Y.I., T.M.), and Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences (M.T., Y.S.), Kumamoto University, Kumamoto, Japan; School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia (V.T.G.C.); Faculty of Pharmaceutical Sciences (K.T., M.O.) and DDS Research Institute (M.O.), Sojo University, Kumamoto, Japan; and Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan (A.I., M.K.).
Motohiko
M
Tanaka
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences (H.M., K.H., H.W., Y.I., V.T.G.C., T.M.), Center for Clinical Pharmaceutical Sciences, School of Pharmacy (H.W., Y.I., T.M.), and Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences (M.T., Y.S.), Kumamoto University, Kumamoto, Japan; School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia (V.T.G.C.); Faculty of Pharmaceutical Sciences (K.T., M.O.) and DDS Research Institute (M.O.), Sojo University, Kumamoto, Japan; and Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan (A.I., M.K.).
Yutaka
Y
Sasaki
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences (H.M., K.H., H.W., Y.I., V.T.G.C., T.M.), Center for Clinical Pharmaceutical Sciences, School of Pharmacy (H.W., Y.I., T.M.), and Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences (M.T., Y.S.), Kumamoto University, Kumamoto, Japan; School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia (V.T.G.C.); Faculty of Pharmaceutical Sciences (K.T., M.O.) and DDS Research Institute (M.O.), Sojo University, Kumamoto, Japan; and Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan (A.I., M.K.).
Masaki
M
Otagiri
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences (H.M., K.H., H.W., Y.I., V.T.G.C., T.M.), Center for Clinical Pharmaceutical Sciences, School of Pharmacy (H.W., Y.I., T.M.), and Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences (M.T., Y.S.), Kumamoto University, Kumamoto, Japan; School of Pharmacy, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia (V.T.G.C.); Faculty of Pharmaceutical Sciences (K.T., M.O.) and DDS Research Institute (M.O.), Sojo University, Kumamoto, Japan; and Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan (A.I., M.K.) tomaru@gpo.kumamoto-u.ac.jp.
Toru
T
Maruyama
D000082:Acetaminophen / Q000494:pharmacology; D000208:Acute Disease; D000418:Albumins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D000975:Antioxidants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D003208:Concanavalin A / Q000494:pharmacology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006023:Glycoproteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D037181:Lectins, C-Type / Q000378:metabolism*; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D000097382:CD68 Molecule
D000082:Acetaminophen; D000418:Albumins; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000975:Antioxidants; D003208:Concanavalin A; D006023:Glycoproteins; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C000596176:SH-Man-HSA protein