Rosiglitazone-loaded nanospheres for modulating macrophage-specific inflammation in obesity

Abstract

PPARγ nuclear receptor agonists have been shown to attenuate macrophage inflammatory responses implicated in the metabolic complications of obesity and in atherosclerosis. However, PPARγ agonists currently in clinical use, including rosiglitazone (RSG), are often associated with severe side effects that limit their therapeutic use. Here, 200 nm PLGA/PVA nanospheres were formulated for the systemic delivery of RSG specifically to macrophages. RSG was encapsulated with over 50% efficiency in the hydrophobic PLGA core and released specifically within the acidifying macrophage phagosomes. In bone marrow derived macrophages, RSG-loaded nanoparticles (RSG-NPs) induce a dose dependent upregulation (1.5 to 2.5-fold) of known PPARγ target genes, with maximal induction at 5 μM; and downregulate the expression of genes related to the inflammatory process, with maximum effect at 10 μM. In Ldlr-/- mice fed high fat diet, treatment with RSG-NPs alleviated inflammation in white adipose tissue and liver but, unlike treatment with free RSG, did not alter genes associated with lipid metabolism or cardiac function, indicating a reduction in the RSG side effect profile. These biocompatible, biodegradable RSG-NPs represent a preliminary step towards the specific delivery of nuclear receptor agonists for the treatment of macrophage-mediated inflammatory conditions associated with obesity, atherosclerosis and other chronic disease states.

Targeting PPARγ in the epigenome rescues genetic metabolic defects in mice

“…Studies of cultured mouse 3T3-L1 adipocytes have shown that Pparg expression is repressed by itazone treatment was insulin sensitizing, despite failing to reduce this inflammatory macrophage signature. There is a rich literature on the antiinflammatory effects of TZDs like rosiglitazone (33), yet in other studies that typically involved longer TZD treatment of obese mice, the decline in inflammatory macrophage markers was often small (less than 2-fold) relative to a large induction of such genes in obesity (31,(43)(44)(45). Indeed, a recent study blocked HFD-induced adipose tissue macrophage recruitment, yet HFD still caused the same degree of obesity and insulin resistance (46).…”

Advances in non-invasive drug delivery for atherosclerotic heart disease

“…Polymeric (PLGA/PVA) nanoparticles Macrophages, reduced hepatic expression of pro-inflammatory genes (high-fat fed LDL receptor KO mice) [66] Paclitaxel, etoposide (topoisomerase inhibitor), methotrexate (anti-folate)…”

“…Di Mascolo et al [66] in a study aimed to prepare the terrain for the use of nuclear receptor agonists in the treatment of atherosclerosis and other inflammation-related conditions, used nanoparticles composed of hydrophobic PLGA polymeric matrix covered by a layer of PVA, a surfactant that lowers surface tension [67]. The PLGA/PVA nanoparticles were used as carriers of rosiglitazone aiming to target macrophages.…”

Opportunities for nanotheranosis in lung cancer and pulmonary metastasis

“…These NPs present a hydrodynamic diameter of about 150 nm, a ξ-potential of −35.0 mV, and are sufficiently small to rely on the EPR effect for tumor accumulation [29–31]. A schematic representation of this type of NP is presented in (Figure 2a).…”

“…For this reason, the resulting NPs are named positron-emitting magnetic nanoconstructs (PEMs). In addition to being used as contrast agents, PEMs have also been loaded with drug molecules, such as docetaxel and rosiglitazone for the treatment of tumors and atherosclerosis, respectively [29]. …”