Sustained zero-order delivery of GC-1 from a nanochannel membrane device alleviates metabolic syndrome.

BACKGROUND/OBJECTIVES: Our objective was to assess the sustained, low-dose and constant administration of the thyroid receptor-ß (TRß)-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. SUBJECTS/METHODS: 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 ß-cell area were assessed. RESULTS: 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 TRß 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 ß-cell area. CONCLUSIONS: 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.

Confinement effects on monosaccharide transport in nanochannels.

Transport theories based on the continuum hypothesis may not be appropriate at the nanoscale in view of surface effects. We employed molecular dynamics simulations to study the effects of confinement and concentration on diffusive transport of glucose in silica nanochannels (10 nm or smaller). We found that glucose modifies the electrical properties of nanochannels and that, below 5 nm in channel height, glucose adsorption and diffusivity are significantly reduced. With increasing concentration, the diffusivity is reduced linearly in the bulk, while it is reduced nonlinearly at the interface. The effective diffusivity reduction is related to the interface thickness, which can be 2-4 nm depending on concentration, and has an unexpected reduction at low concentrations. Results suggest that nanochannels present a one-dimensional cage environment that affects diffusivity in a fashion similar to cage-breaking diffusion. Our simulation results, consistent with the experimental observations presented here, suggest that nanoconfinement is the essential cause of the observed altered fluid diffusive transport, not accounted for by classical theories, because of coupling of confinement and concentration effects.

Nanochannel systems for personalized therapy and laboratory diagnostics.

Significant recent progress has been made in the development of microfabricated nanofluidic devices for use in the biomedical sciences. Novel nanotechnological approaches have been explored in view of a more individualized medical approach. Much of the development has been fuelled by the advantages derived from utilizing nanoscale phenomena to manipulate fluid samples or mediate drug delivery. As such, we present a comprehensive review of nanochannel technologies, highlighting their potential for diagnostic and therapeutic applications.