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Importance of thoro...
Importance of thorough tissue and cellular level characterization of targeted drugs in the evaluation of pharmacodynamic effects
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Bauknight, D. K. (författare)
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Osinski, V. (författare)
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Dasa, S. S. K. (författare)
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visa fler...
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Nguyen, A. T. (författare)
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Marshall, M. A. (författare)
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Hartman, J. (författare)
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Harms, M. (författare)
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O’Mahony, G. (författare)
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- Boucher, Jeremie (författare)
- Gothenburg University,Göteborgs universitet,Wallenberg Centre for Molecular and Translational Medicine
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Klibanov, A. L. (författare)
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McNamara, C. A. (författare)
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Kelly, K. A. (författare)
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(creator_code:org_t)
- 2019-11-14
- 2019
- Engelska.
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:11
- Relaterad länk:
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https://journals.plo...
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Targeted nanoparticle delivery is a promising strategy for increasing efficacy and limiting side effects of therapeutics. When designing a targeted liposomal formulation, the in vivo biodistribution of the particles must be characterized to determine the value of the targeting approach. Peroxisome proliferator-activated receptor (PPAR) agonists effectively treat metabolic syndrome by decreasing dyslipidemia and insulin resistance but side effects have limited their use, making them a class of compounds that could benefit from targeted liposomal delivery. The adipose targeting sequence peptide (ATS) could fit this role, as it has been shown to bind to adipose tissue endothelium and induce weight loss when delivered conjugated to a pro-apoptotic peptide. To date, however, a full assessment of ATS in vivo biodistribution has not been reported, leaving important unanswered questions regarding the exact mechanisms whereby ATS targeting enhances therapeutic efficacy. We designed this study to evaluate the biodistribution of ATS-conjugated liposomes loaded with the PPARα/γ dual agonist tesaglitazar in leptin-deficient ob/ob mice. The ATS-liposome biodistribution in adipose tissue and other organs was examined at the cellular and tissue level using microscopy, flow cytometry, and fluorescent molecular tomography. Changes in metabolic parameters and gene expression were measured by target and off-target tissue responses to the treatment. Unexpectedly, ATS targeting did not increase liposomal uptake in adipose relative to other tissues, but did increase uptake in the kidneys. Targeting also did not significantly alter metabolic parameters. Analysis of the liposome cellular distribution in the stromal vascular fraction with flow cytometry revealed high uptake by multiple cell types. Our findings highlight the need for thorough study of in vivo biodistribution when evaluating a targeted therapy. © 2019 Bauknight et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- leptin
- liposome
- tesaglitazar
- adipocyte
- adipose tissue
- animal cell
- animal experiment
- animal model
- animal tissue
- Article
- cell level
- cell transport
- cellular distribution
- controlled study
- drug blood level
- drug distribution
- drug effect
- drug mechanism
- drug screening
- drug targeting
- drug tissue level
- endothelium
- flow cytometry
- gene expression
- in vivo study
- kidney
- leptin deficiency
- liposomal delivery
- male
- microscopy
- mouse
- nonhuman
- pharmacodynamics
- tissue reaction
- tomography
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
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PLoS ONE
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Till lärosätets databas
- Av författaren/redakt...
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Bauknight, D. K.
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Osinski, V.
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Dasa, S. S. K.
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Nguyen, A. T.
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Marshall, M. A.
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Hartman, J.
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visa fler...
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Harms, M.
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O’Mahony, G.
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Boucher, Jeremie
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Klibanov, A. L.
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McNamara, C. A.
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Kelly, K. 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 ...
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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 Cancer och onkol ...
- Artiklar i publikationen
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PLoS ONE
- Av lärosätet
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Göteborgs universitet