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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. (författare)
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Bauknight, D. K. (författare)
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Dasa, S. S. K. (författare)
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Harms, M. J. (författare)
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Kroon, T. (författare)
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Marshall, M. A. (författare)
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Garmey, J. C. (författare)
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Nguyen, A. T. (författare)
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Hartman, J. (författare)
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Upadhye, A. (författare)
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Srikakulapu, P. (författare)
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Zhou, A. (författare)
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O'Mahony, G. (författare)
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Klibanov, A. L. (författare)
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Kelly, K. A. (författare)
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- Boucher, Jeremie (författare)
- Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory
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McNamara, C. A. (författare)
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(creator_code:org_t)
- Ivyspring International Publisher, 2020
- 2020
- Engelska.
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Ingår i: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 10:2, s. 585-601
- Relaterad länk:
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https://doi.org/10.7...
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https://gup.ub.gu.se...
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https://doi.org/10.7...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Nyckelord
- 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
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas
- Av författaren/redakt...
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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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visa fler...
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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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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Endokrinologi oc ...
- Artiklar i publikationen
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Theranostics
- Av lärosätet
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Göteborgs universitet