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The scope of this project was to design, synthesize and test targeted nanoparticles containing hydrophobic and hydrophilic drugs that promote browning in adipose tissue. For hydrophilic drugs the use of liposomes and their hydrophilic core is more useful than the PLGA nanoparticles which have hydrophobic cores. The inhibition of the FOXO1 pathway and modulation of autophagy in adipose tissue can promote browning of white adipose tissue, or an energy burning state where excess energy is burned as heat instead of stored in the cell. If successful, these drugs would offer an alternative treatment for obesity where changes to the patient's lifestyle, such as dieting and frequent exercise, have had little desired effect. The targeted nature of this treatment offers several potential benefits over free drug doses. For example, the FOXO1 pathway interacts with the insulin signal in cells and the inhibition of this pathway in many cell types throughout the body may have various unintended side-effects. Targeted drug delivery using nanoparticles may result in a more efficient transfer of the drug to the adipose tissue and may allow for a lower active drug-load for treatment. We have successfully synthesized PLGA nanoparticles containing AS1842856 and DMPC/DPPC liposomes containing Balfilomycin-A1 or CL316243 using a turbulent jet mixing approach. A targeting peptide, P3 which binds to prohibitin in white adipose tissue vasculature, was conjugated to the PLGA nanoparticles. The particle size, as measured by dynamic light scattering, was found to range between 140-210nm for the PLGA nanoparticles and 90-220nm for the liposomes. We are currently testing the free drugs and nanoparticle encapsulated drugs using the 3T3 cell line. FOXO1 and autophagy inhibitors can prevent differentiation of 3T3 cells into preadipocytes. The 3T3 cells have been successfully differentiated into preadipocytes as measured using oil red O staining and dose response testing is ongoing. The results will demonstrate whether encapsulation and targeted encapsulation improves the response and/or allows for a lower drug dose as compared to the free drug.
Chemical & Life Science Engineering
Biological Factors | Biotechnology | Cell Biology | Lipids | Medicinal Chemistry and Pharmaceutics | Nanomedicine | Other Chemicals and Drugs
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