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In vivo liposomal d...
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
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Osinski, V. (author)
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Bauknight, D. K. (author)
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Dasa, S. S. K. (author)
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Harms, M. J. (author)
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Kroon, T. (author)
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Marshall, M. A. (author)
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Garmey, J. C. (author)
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Nguyen, A. T. (author)
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Hartman, J. (author)
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Upadhye, A. (author)
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Srikakulapu, P. (author)
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Zhou, A. (author)
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O'Mahony, G. (author)
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Klibanov, A. L. (author)
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Kelly, K. A. (author)
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- Boucher, Jeremie (author)
- Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory
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McNamara, C. A. (author)
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(creator_code:org_t)
- Ivyspring International Publisher, 2020
- 2020
- English.
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In: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 10:2, s. 585-601
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https://doi.org/10.7...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Keyword
- 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
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Osinski, V.
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Bauknight, D. K.
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Dasa, S. S. K.
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Harms, M. J.
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Kroon, T.
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Marshall, M. A.
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show more...
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Garmey, J. C.
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Nguyen, A. T.
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Hartman, J.
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Upadhye, A.
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Srikakulapu, P.
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Zhou, A.
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O'Mahony, G.
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Klibanov, A. L.
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Kelly, K. A.
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Boucher, Jeremie
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McNamara, C. A.
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
- Articles in the publication
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Theranostics
- By the university
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University of Gothenburg