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In vivo liposomal delivery of PPAR alpha/gamma dual agonist tesaglitazar in a model of obesity enriches macrophage targeting and limits liver and kidney drug effects

Artikel i vetenskaplig tidskrift
Författare V. Osinski
D. K. Bauknight
S. S. K. Dasa
M. J. Harms
T. Kroon
M. A. Marshall
J. C. Garmey
A. T. Nguyen
J. Hartman
A. Upadhye
P. Srikakulapu
A. Zhou
G. O'Mahony
A. L. Klibanov
K. A. Kelly
Jeremie Boucher
C. A. McNamara
Publicerad i Theranostics
Volym 10
Nummer/häfte 2
Sidor 585-601
ISSN 1838-7640
Publiceringsår 2020
Publicerad vid Wallenberglaboratoriet
Sidor 585-601
Språk en
Länkar dx.doi.org/10.7150/thno.36572
Ämnesord liposomes, tesaglitazar, peroxisome proliferator-activated receptors, obesity-associated dysmetabolism, macrophages, activated receptor-gamma, monocyte chemoattractant protein-1, adipose-tissue macrophages, insulin-resistance, hepatic steatosis, dendritic cells, renal-function, t-cells, alpha, polarization, Research & Experimental Medicine
Ämneskategorier Endokrinologi och diabetes

Sammanfattning

Macrophages are important regulators of obesity-associated inflammation and PPAR alpha and -gamma agonism in macrophages has anti-inflammatory effects. In this study, we tested the efficacy with which liposomal delivery could target the PPAR alpha/gamma dual agonist tesaglitazar to macrophages while reducing drug action in common sites of drug toxicity: the liver and kidney, and whether tesaglitazar had anti-inflammatory effects in an in vivo model of obesity-associated dysmetabolism. Methods: Male leptin-deficient (ob/ob) mice were administered tesaglitazar or vehicle for one week in a standard oral formulation or encapsulated in liposomes. Following the end of treatment, circulating metabolic parameters were measured and pro-inflammatory adipose tissue macrophage populations were quantified by flow cytometry. Cellular uptake of liposomes in tissues was assessed using immunofluorescence and a broad panel of cell subset markers by flow cytometry. Finally, PPAR alpha/gamma gene target expression levels in the liver, kidney, and sorted macrophages were quantified to determine levels of drug targeting to and drug action in these tissues and cells. Results: Administration of a standard oral formulation of tesaglitazar effectively treated symptoms of obesity-associated dysmetabolism and reduced the number of pro-inflammatory adipose tissue macrophages. Macrophages are the major cell type that took up liposomes with many other immune and stromal cell types taking up liposomes to a lesser extent. Liposome delivery of tesaglitazar did not have effects on inflammatory macrophages nor did it improve metabolic parameters to the extent of a standard oral formulation. Liposomal delivery did, however, attenuate effects on liver weight and liver and kidney expression of PPAR alpha and -gamma gene targets compared to oral delivery. Conclusions: These findings reveal for the first time that tesaglitazar has anti-inflammatory effects on adipose tissue macrophage populations in vivo. These data also suggest that while nanoparticle delivery reduced off-target effects, yet the lack of tesaglitazar actions in non-targeted cells such (as hepatocytes and adipocytes) and the uptake of drug-loaded liposomes in many other cell types, albeit to a lesser extent, may have impacted overall therapeutic efficacy. This fulsome analysis of cellular uptake of tesaglitazar-loaded liposomes provides important lessons for future studies of liposome drug delivery.

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Utskriftsdatum: 2020-05-30