title: Targeted Therapy for Acute Autoimmune Myocarditis with Nano-Sized Liposomal FK506 in Rats.
abstract: Immunosuppressive agents are used for the treatment of immune-mediated myocarditis; however, the need to develop a more effective therapeutic approach remains. Nano-sized liposomes may accumulate in and selectively deliver drugs to an inflammatory lesion with enhanced vascular permeability. The aims of this study were to investigate the distribution of liposomal FK506, an immunosuppressive drug encapsulated within liposomes, and the drug's effects on cardiac function in a rat experimental autoimmune myocarditis (EAM) model. We prepared polyethylene glycol-modified liposomal FK506 (mean diameter: 109.5 ± 4.4 nm). We induced EAM by immunization with porcine myosin and assessed the tissue distribution of the nano-sized beads and liposomal FK506 in this model. After liposomal or free FK506 was administered on days 14 and 17 after immunization, the cytokine expression in the rat hearts along with the histological findings and hemodynamic parameters were determined on day 21. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads had accumulated in myocarditic but not normal hearts on day 14 after immunization and thereafter. Compared to the administration of free FK506, FK506 levels were increased in both the plasma and hearts of EAM rats when liposomal FK506 was administered. The administration of liposomal FK506 markedly suppressed the expression of cytokines, such as interferon-γ and tumor necrosis factor-α, and reduced inflammation and fibrosis in the myocardium on day 21 compared to free FK506. The administration of liposomal FK506 also markedly ameliorated cardiac dysfunction on day 21 compared to free FK506. Nano-sized liposomes may be a promising drug delivery system for targeting myocarditic hearts with cardioprotective agents.
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Keiji
authors: K
authors: Okuda
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Hai Ying
authors: HY
authors: Fu
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Takashi
authors: T
authors: Matsuzaki
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Ryo
authors: R
authors: Araki
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Shota
authors: S
authors: Tsuchida
authors: Department of Pharmaceutical Chemistry, International Medical University, Kuala Lumpur, Malaysia.
authors: Punniyakoti V
authors: PV
authors: Thanikachalam
authors: Department of Medical Biochemistry, University of Shizuoka Graduate School of Pharmaceutical Sciences, Shizuoka, Japan.
authors: Tatsuya
authors: T
authors: Fukuta
authors: Department of Medical Biochemistry, University of Shizuoka Graduate School of Pharmaceutical Sciences, Shizuoka, Japan.
authors: Tomohiro
authors: T
authors: Asai
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Masaki
authors: M
authors: Yamato
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Shoji
authors: S
authors: Sanada
authors: Department of Internal Medicine, Meiji University of Integrative Medicine, Nantan, Kyoto, Japan.
authors: Hiroshi
authors: H
authors: Asanuma
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Yoshihiro
authors: Y
authors: Asano
authors: Clinical Research and Development, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
authors: Masanori
authors: M
authors: Asakura
authors: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors: Haruo
authors: H
authors: Hanawa
authors: Department of Pathology, Nihon University School of Medicine, Tokyo, Japan.
authors: Hiroyuki
authors: H
authors: Hao
authors: Department of Medical Biochemistry, University of Shizuoka Graduate School of Pharmaceutical Sciences, Shizuoka, Japan.
authors: Naoto
authors: N
authors: Oku
authors: Department of Medical Biochemistry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Seiji
authors: S
authors: Takashima
authors: Clinical Research and Development, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
authors: Masafumi
authors: M
authors: Kitakaze
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors: Yasushi
authors: Y
authors: Sakata
authors: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan.
authors: Tetsuo
authors: T
authors: Minamino
mesh_terms: D000208:Acute Disease; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D009205:Myocarditis / Q000188:drug therapy* / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D008081:Liposomes; D016559:Tacrolimus