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Sökning: WFRF:(O'Mahony D) > (2020-2024) > In vivo liposomal d...

  • Osinski, V. (författare)

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/kapitelEngelska2020

Förlag, utgivningsår, omfång ...

  • Ivyspring International Publisher,2020

Nummerbeteckningar

  • LIBRIS-ID:oai:gup.ub.gu.se/287855
  • https://gup.ub.gu.se/publication/287855URI
  • https://doi.org/10.7150/thno.36572DOI

Kompletterande språkuppgifter

  • Språk:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • 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 och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Bauknight, D. K. (författare)
  • Dasa, S. S. K. (författare)
  • Harms, M. J. (författare)
  • Kroon, T. (författare)
  • Marshall, M. A. (författare)
  • Garmey, J. C. (författare)
  • Nguyen, A. T. (författare)
  • Hartman, J. (författare)
  • Upadhye, A. (författare)
  • Srikakulapu, P. (författare)
  • Zhou, A. (författare)
  • O'Mahony, G. (författare)
  • Klibanov, A. L. (författare)
  • Kelly, K. A. (författare)
  • Boucher, JeremieGothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory(Swepub:gu)xbouje (författare)
  • McNamara, C. A. (författare)
  • Göteborgs universitetWallenberglaboratoriet (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Theranostics: Ivyspring International Publisher10:2, s. 585-6011838-7640

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