Self-assembling lisofylline-fatty acid conjugate for effective treatment of diabetes mellitus

Kishan S. Italiya, Samrat Mazumdar, Saurabh Sharma, Deepak Chitkara, Ram I Mahato, Anupama Mittal

Research output: Contribution to journalArticle

Abstract

Lisofylline is an anti-inflammatory agent with proven anti-diabetic activity. Its high solubility and rapid metabolism results in poor bioavailability and short half-life, limiting its clinical utility. We have synthesized Lisofylline-Linoleic acid (LSF-LA) conjugate which self-assembled into micelles (156.9 nm; PDI 0.187; CMC 1 μg/mL; aggregation number 54) without any surfactant and showed enhanced cellular uptake. It protected MIN6 insulinoma cells from cytokine induced cell death and enhanced insulin production under inflammatory conditions. It also suppressed the proliferation of activated peripheral blood mononuclear cells and reduced the production of inflammatory cytokines, IFN-γ and TNF-α. LSF-LA micelles exhibited reduced protein binding, significantly higher half-life (5.7-fold) and higher apparent volume of distribution (5.3-fold) than free LSF. In T1D animals, reduced blood glucose levels were observed at a reduced dose (~15 mg/kg, once daily of LSF-LA micelles vs. 25 mg/kg, twice daily of free LSF) that was further confirmed by immunohistochemical analysis.

LanguageEnglish (US)
Pages175-187
Number of pages13
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

lisofylline
Linoleic acid
Medical problems
Fatty acids
Micelles
Diabetes Mellitus
Linoleic Acid
Fatty Acids
Blood
Half-Life
Insulin
Cell death
Cytokines
Metabolism
Insulinoma
Glucose
Animals
Surface active agents
Agglomeration
Solubility

Keywords

  • Diabetes
  • Linoleic acid
  • Lisofylline
  • Pharmacokinetics
  • Self-assembly

ASJC Scopus subject areas

  • Bioengineering
  • Medicine (miscellaneous)
  • Molecular Medicine
  • Biomedical Engineering
  • Materials Science(all)
  • Pharmaceutical Science

Cite this

Self-assembling lisofylline-fatty acid conjugate for effective treatment of diabetes mellitus. / Italiya, Kishan S.; Mazumdar, Samrat; Sharma, Saurabh; Chitkara, Deepak; Mahato, Ram I; Mittal, Anupama.

In: Nanomedicine: Nanotechnology, Biology, and Medicine, Vol. 15, No. 1, 01.01.2019, p. 175-187.

Research output: Contribution to journalArticle

Italiya, Kishan S. ; Mazumdar, Samrat ; Sharma, Saurabh ; Chitkara, Deepak ; Mahato, Ram I ; Mittal, Anupama. / Self-assembling lisofylline-fatty acid conjugate for effective treatment of diabetes mellitus. In: Nanomedicine: Nanotechnology, Biology, and Medicine. 2019 ; Vol. 15, No. 1. pp. 175-187.
@article{c76643ffaf2c400098e043afd8a003d4,
title = "Self-assembling lisofylline-fatty acid conjugate for effective treatment of diabetes mellitus",
abstract = "Lisofylline is an anti-inflammatory agent with proven anti-diabetic activity. Its high solubility and rapid metabolism results in poor bioavailability and short half-life, limiting its clinical utility. We have synthesized Lisofylline-Linoleic acid (LSF-LA) conjugate which self-assembled into micelles (156.9 nm; PDI 0.187; CMC 1 μg/mL; aggregation number 54) without any surfactant and showed enhanced cellular uptake. It protected MIN6 insulinoma cells from cytokine induced cell death and enhanced insulin production under inflammatory conditions. It also suppressed the proliferation of activated peripheral blood mononuclear cells and reduced the production of inflammatory cytokines, IFN-γ and TNF-α. LSF-LA micelles exhibited reduced protein binding, significantly higher half-life (5.7-fold) and higher apparent volume of distribution (5.3-fold) than free LSF. In T1D animals, reduced blood glucose levels were observed at a reduced dose (~15 mg/kg, once daily of LSF-LA micelles vs. 25 mg/kg, twice daily of free LSF) that was further confirmed by immunohistochemical analysis.",
keywords = "Diabetes, Linoleic acid, Lisofylline, Pharmacokinetics, Self-assembly",
author = "Italiya, {Kishan S.} and Samrat Mazumdar and Saurabh Sharma and Deepak Chitkara and Mahato, {Ram I} and Anupama Mittal",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.nano.2018.09.014",
language = "English (US)",
volume = "15",
pages = "175--187",
journal = "Nanomedicine: Nanotechnology, Biology, and Medicine",
issn = "1549-9634",
publisher = "Elsevier Inc.",
number = "1",

}

TY - JOUR

T1 - Self-assembling lisofylline-fatty acid conjugate for effective treatment of diabetes mellitus

AU - Italiya, Kishan S.

AU - Mazumdar, Samrat

AU - Sharma, Saurabh

AU - Chitkara, Deepak

AU - Mahato, Ram I

AU - Mittal, Anupama

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Lisofylline is an anti-inflammatory agent with proven anti-diabetic activity. Its high solubility and rapid metabolism results in poor bioavailability and short half-life, limiting its clinical utility. We have synthesized Lisofylline-Linoleic acid (LSF-LA) conjugate which self-assembled into micelles (156.9 nm; PDI 0.187; CMC 1 μg/mL; aggregation number 54) without any surfactant and showed enhanced cellular uptake. It protected MIN6 insulinoma cells from cytokine induced cell death and enhanced insulin production under inflammatory conditions. It also suppressed the proliferation of activated peripheral blood mononuclear cells and reduced the production of inflammatory cytokines, IFN-γ and TNF-α. LSF-LA micelles exhibited reduced protein binding, significantly higher half-life (5.7-fold) and higher apparent volume of distribution (5.3-fold) than free LSF. In T1D animals, reduced blood glucose levels were observed at a reduced dose (~15 mg/kg, once daily of LSF-LA micelles vs. 25 mg/kg, twice daily of free LSF) that was further confirmed by immunohistochemical analysis.

AB - Lisofylline is an anti-inflammatory agent with proven anti-diabetic activity. Its high solubility and rapid metabolism results in poor bioavailability and short half-life, limiting its clinical utility. We have synthesized Lisofylline-Linoleic acid (LSF-LA) conjugate which self-assembled into micelles (156.9 nm; PDI 0.187; CMC 1 μg/mL; aggregation number 54) without any surfactant and showed enhanced cellular uptake. It protected MIN6 insulinoma cells from cytokine induced cell death and enhanced insulin production under inflammatory conditions. It also suppressed the proliferation of activated peripheral blood mononuclear cells and reduced the production of inflammatory cytokines, IFN-γ and TNF-α. LSF-LA micelles exhibited reduced protein binding, significantly higher half-life (5.7-fold) and higher apparent volume of distribution (5.3-fold) than free LSF. In T1D animals, reduced blood glucose levels were observed at a reduced dose (~15 mg/kg, once daily of LSF-LA micelles vs. 25 mg/kg, twice daily of free LSF) that was further confirmed by immunohistochemical analysis.

KW - Diabetes

KW - Linoleic acid

KW - Lisofylline

KW - Pharmacokinetics

KW - Self-assembly

UR - http://www.scopus.com/inward/record.url?scp=85055671412&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055671412&partnerID=8YFLogxK

U2 - 10.1016/j.nano.2018.09.014

DO - 10.1016/j.nano.2018.09.014

M3 - Article

VL - 15

SP - 175

EP - 187

JO - Nanomedicine: Nanotechnology, Biology, and Medicine

T2 - Nanomedicine: Nanotechnology, Biology, and Medicine

JF - Nanomedicine: Nanotechnology, Biology, and Medicine

SN - 1549-9634

IS - 1

ER -