Abstract 19172: Nanoparticle Delivery of Rosiglitazone Confers Tissue-Selective PPARgamma Activation
Thiazolidinediones (TZDs) are potent, high-affinity PPARγ ligands widely used to promote insulin sensitivity that act, at least in part, by decreasing myeloid-mediated inflammatory processes. However, treatment with TZDs such as rosiglitazone (RSG) can promote edema, weight gain and cardiac failure, limiting their clinical utility. We hypothesized that RSG-loaded nanoparticles could reduce these side-effects by conferring tissue-selective drug delivery. To test this hypothesis we developed a methodology to engulf RSG in ~100nm polylactic-co-glycolic acid (PLGA) particles extensively used for nanoparticle based therapies. These particles are rapidly cleared from the circulation by phagocytic cells, and thus accumulate in tissues enriched in myeloid-lineage cells, such as liver, spleen and potentially atherosclerotic plaques and remodeling white adipose tissue (WAT) of obese subjects. To test the effects of RSG-loaded nanoparticles in vivo, male LDLR-/- mice (N=3-4/group) were randomly assigned to 1) high-fat diet (HFD) alone, 2) HFD supplemented with RSG (1.2g RSG/kg diet), or HFD and then retro-orbitally injected on days 1 and 2 with 100µg of nanoparticles containing 3) PLGA alone or 4) PLGA loaded with 50µg RSG (PLGA:RSG). Tissue samples were collected at day 3 post-treatment. RT-PCR analysis of PPARγ target genes found RSG, but not PLGA:RSG or PLGA, increased (P<0.05) WAT expression of ABCG1 and CD36 and kidney expression of SCNN1A, which may contribute to TZD-mediated edema. RSG and PLGA:RSG, but not PLGA, induced FABP4 in spleen and increased or trended to increase (P<0.01) ACO1, CD36 and FABP4 in liver. RT-PCR analysis of tissue samples obtained at day 6 post treatment also found increases or trends to increase in liver expression of CD36 and FABP4 in PLGA:RSG treated mice, indicating that RSG-inducible gene expression in whole-tissue persisted for at least 4 days post-treatment, and might persist longer in myeloid populations within this tissue. Taken together this data indicates that our PLGA nanoparticles can be used to selectively target RSG-mediated gene activation to specific tissues, and thus may represent a novel approach for targeting drug delivery to myeloid-rich tissues or sites, such as inflamed WAT or atherosclerotic plaque.
- © 2012 by American Heart Association, Inc.