Harnessing Monocytes for a Liposomal Rosiglitazone-Mediated Anti-Inflammatory Effect

Rosiglitazone, an anti-diabetic drug used for treating type Ⅱ diabetes mellitus with known anti-inflammatory properties, was withdrawn from the European market. The United States Food and Drug Administration has restricted its use due to its severe cardiovascular adverse effects. We hypothesized that rosiglitazone could be repurposed to provide safe anti-inflammatory therapy. By encapsulating the drug in liposomes internalized preferentially by circulating monocytes, monocytes’ inhibition can be achieved while avoiding the inherent systemic side effects. Rosiglitazone was loaded into empty liposomes by an active loading method. The formulation (LipRosi) was developed with desirable physicochemical properties promoting preferential monocyte internalization via membrane surface negative charge. Appropriate physicochemical properties include nano-size, low polydispersity index (PDI), high drug loading capacity, high encapsulation yield, and shelf-life stability. Further, these liposomes exhibited time-and concentration-dependent uptake in a murine monocyte/macrophage cell line (RAW264.7). In addition, LipRosi was found to be significantly more effective in depleting monocytes than drug-free liposomes and the free drug in solution. A cytotoxic effect on smooth muscle cells was only observed at the highest concentration examined and after an extended exposure time. In vivo studies in rats demonstrated a time-dependent uptake by intact circulating white blood cells (WBC), primarily monocytes. Administration of 20 mg/kg LipRosi, injected on two consecutive days, achieved a therapeutic window of monocyte depletion after 24 hr. Of note, only a dismal disposition of the formulation was detected in the heart. Since monocytes play a central role in the progression of inflammatory related-disorders, LipRosi could be found therapeutic for multiple disorders.