Inhibition of keratinocyte proliferation by phospholipid-conjugates of a TLR7 ligand in a Myc-induced hyperplastic actinic keratosis model in the absence of systemic side effects

Eur J Dermatol. 2013 Sep-Oct;23(5):618-28. doi: 10.1684/ejd.2013.2155.

Abstract

Background: The Toll-like receptor 7 (TLR7) activator imiquimod (IMQ) is safe and effective in treating actinic keratosis; however, an intermittent treatment regimen is necessary because of excessive local reactions.

Objectives: To evaluate in vitro potency, pharmacodynamics/pharmacokinetics, toxicity and efficacy in vivo of the newly developed TLR7 ligand-phospholipid conjugate, TMX-202, in a gel formulation.

Material and methods: The effects of TMX-202 were assessed both in vitro on a murine macrophage cell line and in primary bone marrow-derived dendritic cells and in vivo on mice (C57BL/6-wild type, Myd88(-/-) and Tlr7(-/-)).

Results: TMX-202 was more potent than IMQ in vitro using murine and human cells. In contrast, in vivo it showed less systemic pro-inflammatory activity and better safety than IMQ. Moreover, the TMX-202 gel formulation exhibited at least comparable efficacy to Aldara in a mouse model for skin proliferative diseases.

Conclusion: TMX-202 is safe and efficacious without causing excessive adverse effects, suggesting that it may be an alternative to Aldara for the treatment of proliferative skin conditions.

Keywords: Myc; Toll like receptor-7; skin proliferative disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / blood
  • Adenine / pharmacology
  • Adenine / therapeutic use
  • Aminoquinolines / blood
  • Aminoquinolines / pharmacology
  • Animals
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use*
  • Cell Line
  • Cell Proliferation / drug effects*
  • Chemotactic Factors / blood
  • Dendritic Cells / physiology
  • Gels / pharmacology
  • Gels / therapeutic use
  • Glycerophospholipids / blood
  • Glycerophospholipids / pharmacology*
  • Glycerophospholipids / therapeutic use*
  • Humans
  • Imiquimod
  • Interferon-gamma / metabolism
  • Interleukin-1 / metabolism
  • Interleukin-6 / metabolism
  • Keratinocytes / physiology
  • Keratosis, Actinic / drug therapy*
  • Keratosis, Actinic / genetics
  • Leukocytes, Mononuclear / drug effects
  • Macrophages / physiology
  • Maximum Tolerated Dose
  • Membrane Glycoproteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myeloid Differentiation Factor 88 / genetics
  • Proto-Oncogene Proteins c-myc / genetics
  • Toll-Like Receptor 7 / genetics*
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Aminoquinolines
  • Antineoplastic Agents
  • Chemotactic Factors
  • Gels
  • Glycerophospholipids
  • Interleukin-1
  • Interleukin-6
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Proto-Oncogene Proteins c-myc
  • TMX-202
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Adenine
  • Imiquimod