title: Sustained zero-order delivery of GC-1 from a nanochannel membrane device alleviates metabolic syndrome.
abstract: Our objective was to assess the sustained, low-dose and constant administration of the thyroid receptor-β (TRβ)-selective agonist GC-1 (sobetirome) from a novel nanochannel membrane device (NMD) for drug delivery. As it known to speed up metabolism, accomplish weight loss, improve cholesterol levels and possess anti-diabetic effects, GC-1 was steadily administered by our NMD, consisting of an implantable nanochannel membrane, as an alternative to conventional daily administration, which is subject to compliance issues in clinical settings.
  
  
  
  Diet-induced obese C57BL/J6 male mice were fed a very high-fat diet (VHFD) and received NMD implants subcutaneously. Ten mice per group received capsules containing GC-1 or phosphate-buffered saline (control). Weight, lean and fat mass, as well as cholesterol, triglycerides, insulin and glucose, were monitored for 24 days. After treatment, plasma levels of thyroid-stimulating hormone (TSH) and thyroxine were compared. mRNA levels of a panel of thermogenic markers were examined using real-time PCR in white adipose tissue (WAT) and brown adipose tissue (BAT). Adipose tissue, liver and local inflammatory response to the implant were examined histologically. Pancreatic islet number and β-cell area were assessed.
  
  
  
  GC-1 released from the NMD reversed VHFD-induced obesity and normalized serum cholesterol and glycemia. Significant reductions in body weight and fat mass were observed within 10 days, whereas reductions in serum cholesterol and glucose levels were seen within 7 days. The significant decrease in TSH was consistent with TRβ selectivity for GC-1. Levels of transcript for Ucp1 and thermogenic genes PGC1a, Cidea, Dio2 and Cox5a showed significant upregulation in WAT in NMD-GC-1-treated mice, but decreased in BAT. Although mice treated by NMD-GC-1 showed a similar number of pancreatic islets, they exhibited significant increase in β-cell area.
  
  
  
  Our data demonstrate that the NMD implant achieves steady administration of GC-1, offering an effective and tightly controlled molecular delivery system for treatment of obesity and metabolic disease, thereby addressing compliance.
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Filgueira
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Nicolov
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Hood
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA.|Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Ballerini
authors.affiliation: Deparment of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Garcia-Huidobro
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: J Z
authors.initials: JZ
authors.lastname: Lin
authors.affiliation: Department of Surgery, The Methodist Hospital, Houston, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Fraga
authors.affiliation: Genomic Medicine Program, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Webb
authors.affiliation: Department of Surgery, The Methodist Hospital, Houston, TX, USA.|Department of Surgery, Weill Cornell Medical College, New York, NY, USA.
authors.forename: O M
authors.initials: OM
authors.lastname: Sabek
authors.affiliation: Department of Surgery, The Methodist Hospital, Houston, TX, USA.|Department of Surgery, Weill Cornell Medical College, New York, NY, USA.
authors.forename: A O
authors.initials: AO
authors.lastname: Gaber
authors.affiliation: Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Phillips
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Grattoni
mesh_terms: D000085:Acetates / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D058990:Molecular Targeted Therapy; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D010636:Phenols / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D037042:Thyroid Hormone Receptors beta / Q000819:agonists*
chemical_list: D000085:Acetates; C413355:GC 1 compound; D010636:Phenols; D037042:Thyroid Hormone Receptors beta