Promoting intestinal lymphatic transport targets a liver-X receptor (LXR) agonist (WAY-252,623) to lymphocytes and enhances immunomodulation

Enyuan Cao, Anna Lindgren, Sofia Martinsson, Luojuan Hu, Lennart Lindfors, Kalle Sigfridsson, Urban Skantze, Erik Michaëlsson, Natalie L. Trevaskis, Christopher J.H. Porter

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Lymphocytes play a central role in the pathology of a range of chronic conditions such as autoimmune disease, transplant rejection, leukemia, lymphoma HIV/AIDs and cardiometabolic diseases such as atherosclerosis. Current treatments for lymphocyte-associated conditions are incompletely effective and/or complicated by a range of off-target toxicities. One major challenge is poor drug access to lymphocytes via the systemic blood and this may be attributed, at least in part, to the fact that lymphocytes are concentrated within lymph fluid and lymphoid tissues, particularly in gut-associated lymphatics. Here we demonstrate that promoting drug uptake into the intestinal lymphatics with a long chain fatty acid, thereby increasing lymphocyte access, enhances the pharmacodynamic effect of a highly lipophilic liver X receptor (LXR) agonist, WAY-252623, that has been suggested as a potential treatment for atherosclerosis. This has been exemplified by: (1) increased mRNA expression of key markers of LXR activation (ABCA1) and regulatory T cells (Foxp3) in local lymphatic lymphocytes and (2) enhanced numbers of CD4+CD25+Foxp3+ regulatory T cells in the systemic circulation, after administration of a 5-fold lower dose with a lymph directing lipid formulation when compared with a non-lipid containing formulation. These data suggest that combining lipophilic, lymphotropic drug candidates such as WAY-252,623, with lymph-directing long chain lipid based formulations can enhance drug targeting to, and activity on, lymphocytes in lymph and that this effect persists through to the systemic circulation. This presents a promising approach to achieve more selective and effective therapeutic outcomes for the treatment of lymphocyte associated diseases.

Original languageEnglish
Pages (from-to)29-39
Number of pages11
JournalJournal of Controlled Release
Volume296
DOIs
Publication statusPublished - 28 Feb 2019

Keywords

  • Atherosclerosis
  • Drug targeting
  • Lipid based drug delivery system
  • Lipophilic drugs
  • Lymphatic transport
  • Lymphocyte

Cite this

@article{35efd68b923f416095458a8d59939e3b,
title = "Promoting intestinal lymphatic transport targets a liver-X receptor (LXR) agonist (WAY-252,623) to lymphocytes and enhances immunomodulation",
abstract = "Lymphocytes play a central role in the pathology of a range of chronic conditions such as autoimmune disease, transplant rejection, leukemia, lymphoma HIV/AIDs and cardiometabolic diseases such as atherosclerosis. Current treatments for lymphocyte-associated conditions are incompletely effective and/or complicated by a range of off-target toxicities. One major challenge is poor drug access to lymphocytes via the systemic blood and this may be attributed, at least in part, to the fact that lymphocytes are concentrated within lymph fluid and lymphoid tissues, particularly in gut-associated lymphatics. Here we demonstrate that promoting drug uptake into the intestinal lymphatics with a long chain fatty acid, thereby increasing lymphocyte access, enhances the pharmacodynamic effect of a highly lipophilic liver X receptor (LXR) agonist, WAY-252623, that has been suggested as a potential treatment for atherosclerosis. This has been exemplified by: (1) increased mRNA expression of key markers of LXR activation (ABCA1) and regulatory T cells (Foxp3) in local lymphatic lymphocytes and (2) enhanced numbers of CD4+CD25+Foxp3+ regulatory T cells in the systemic circulation, after administration of a 5-fold lower dose with a lymph directing lipid formulation when compared with a non-lipid containing formulation. These data suggest that combining lipophilic, lymphotropic drug candidates such as WAY-252,623, with lymph-directing long chain lipid based formulations can enhance drug targeting to, and activity on, lymphocytes in lymph and that this effect persists through to the systemic circulation. This presents a promising approach to achieve more selective and effective therapeutic outcomes for the treatment of lymphocyte associated diseases.",
keywords = "Atherosclerosis, Drug targeting, Lipid based drug delivery system, Lipophilic drugs, Lymphatic transport, Lymphocyte",
author = "Enyuan Cao and Anna Lindgren and Sofia Martinsson and Luojuan Hu and Lennart Lindfors and Kalle Sigfridsson and Urban Skantze and Erik Micha{\"e}lsson and Trevaskis, {Natalie L.} and Porter, {Christopher J.H.}",
year = "2019",
month = "2",
day = "28",
doi = "10.1016/j.jconrel.2019.01.002",
language = "English",
volume = "296",
pages = "29--39",
journal = "Journal of Controlled Release",
issn = "0168-3659",
publisher = "Elsevier",

}

Promoting intestinal lymphatic transport targets a liver-X receptor (LXR) agonist (WAY-252,623) to lymphocytes and enhances immunomodulation. / Cao, Enyuan; Lindgren, Anna; Martinsson, Sofia; Hu, Luojuan; Lindfors, Lennart; Sigfridsson, Kalle; Skantze, Urban; Michaëlsson, Erik; Trevaskis, Natalie L.; Porter, Christopher J.H.

In: Journal of Controlled Release, Vol. 296, 28.02.2019, p. 29-39.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Promoting intestinal lymphatic transport targets a liver-X receptor (LXR) agonist (WAY-252,623) to lymphocytes and enhances immunomodulation

AU - Cao, Enyuan

AU - Lindgren, Anna

AU - Martinsson, Sofia

AU - Hu, Luojuan

AU - Lindfors, Lennart

AU - Sigfridsson, Kalle

AU - Skantze, Urban

AU - Michaëlsson, Erik

AU - Trevaskis, Natalie L.

AU - Porter, Christopher J.H.

PY - 2019/2/28

Y1 - 2019/2/28

N2 - Lymphocytes play a central role in the pathology of a range of chronic conditions such as autoimmune disease, transplant rejection, leukemia, lymphoma HIV/AIDs and cardiometabolic diseases such as atherosclerosis. Current treatments for lymphocyte-associated conditions are incompletely effective and/or complicated by a range of off-target toxicities. One major challenge is poor drug access to lymphocytes via the systemic blood and this may be attributed, at least in part, to the fact that lymphocytes are concentrated within lymph fluid and lymphoid tissues, particularly in gut-associated lymphatics. Here we demonstrate that promoting drug uptake into the intestinal lymphatics with a long chain fatty acid, thereby increasing lymphocyte access, enhances the pharmacodynamic effect of a highly lipophilic liver X receptor (LXR) agonist, WAY-252623, that has been suggested as a potential treatment for atherosclerosis. This has been exemplified by: (1) increased mRNA expression of key markers of LXR activation (ABCA1) and regulatory T cells (Foxp3) in local lymphatic lymphocytes and (2) enhanced numbers of CD4+CD25+Foxp3+ regulatory T cells in the systemic circulation, after administration of a 5-fold lower dose with a lymph directing lipid formulation when compared with a non-lipid containing formulation. These data suggest that combining lipophilic, lymphotropic drug candidates such as WAY-252,623, with lymph-directing long chain lipid based formulations can enhance drug targeting to, and activity on, lymphocytes in lymph and that this effect persists through to the systemic circulation. This presents a promising approach to achieve more selective and effective therapeutic outcomes for the treatment of lymphocyte associated diseases.

AB - Lymphocytes play a central role in the pathology of a range of chronic conditions such as autoimmune disease, transplant rejection, leukemia, lymphoma HIV/AIDs and cardiometabolic diseases such as atherosclerosis. Current treatments for lymphocyte-associated conditions are incompletely effective and/or complicated by a range of off-target toxicities. One major challenge is poor drug access to lymphocytes via the systemic blood and this may be attributed, at least in part, to the fact that lymphocytes are concentrated within lymph fluid and lymphoid tissues, particularly in gut-associated lymphatics. Here we demonstrate that promoting drug uptake into the intestinal lymphatics with a long chain fatty acid, thereby increasing lymphocyte access, enhances the pharmacodynamic effect of a highly lipophilic liver X receptor (LXR) agonist, WAY-252623, that has been suggested as a potential treatment for atherosclerosis. This has been exemplified by: (1) increased mRNA expression of key markers of LXR activation (ABCA1) and regulatory T cells (Foxp3) in local lymphatic lymphocytes and (2) enhanced numbers of CD4+CD25+Foxp3+ regulatory T cells in the systemic circulation, after administration of a 5-fold lower dose with a lymph directing lipid formulation when compared with a non-lipid containing formulation. These data suggest that combining lipophilic, lymphotropic drug candidates such as WAY-252,623, with lymph-directing long chain lipid based formulations can enhance drug targeting to, and activity on, lymphocytes in lymph and that this effect persists through to the systemic circulation. This presents a promising approach to achieve more selective and effective therapeutic outcomes for the treatment of lymphocyte associated diseases.

KW - Atherosclerosis

KW - Drug targeting

KW - Lipid based drug delivery system

KW - Lipophilic drugs

KW - Lymphatic transport

KW - Lymphocyte

UR - http://www.scopus.com/inward/record.url?scp=85060105668&partnerID=8YFLogxK

U2 - 10.1016/j.jconrel.2019.01.002

DO - 10.1016/j.jconrel.2019.01.002

M3 - Article

VL - 296

SP - 29

EP - 39

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

ER -