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Studying Wnt Signaling During Patterning of Conducting Airways
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Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes

Pedro P G Guimaraes1, Mingchee Tan2, Tuomas Tammela3

  • 1Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, United States; Department of Chemical Engineering, MIT, Cambridge, MA, United States; Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States.

Journal of Controlled Release : Official Journal of the Controlled Release Society
|October 6, 2018
PubMed

Insights

Host-guest chemistry enhances LGK974 solubility and bioavailability. This Wnt signaling inhibitor shows promise for safer lung cancer treatment with reduced toxicity.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • Wnt signaling pathway activation drives lung cancer progression and poor prognosis.
  • LGK974, an orally bioavailable porcupine inhibitor, effectively suppresses Wnt signaling but faces limitations due to low solubility and high toxicity.
  • Targeting Wnt signaling is crucial for effective cancer therapeutics.

Purpose of the Study:

  • To enhance the solubility and bioavailability of LGK974 using host-guest chemistry with cyclodextrins (CD).
  • To evaluate the efficacy of CD:LGK974 complexes in inhibiting Wnt signaling in lung adenocarcinoma models.
  • To assess the safety profile and therapeutic potential of these complexes for cancer treatment.

Main Methods:

  • Host-guest complexation of LGK974 with cyclodextrins (CD) confirmed by 2D 1H NMR.
  • In vitro assessment of Wnt target gene expression in lung cancer organoids.
  • In vivo evaluation in mouse lung cancer allograft models, including bioavailability and toxicity studies.

Main Results:

  • CD:LGK974 complexes significantly reduced Wnt target gene expression in lung cancer organoids and allografts.
  • Complexation with CDs enhanced LGK974 oral bioavailability in mice.
  • CD:LGK974 complexes demonstrated potent Wnt signaling inhibition with reduced intestinal toxicity compared to free LGK974.

Conclusions:

  • Host-guest chemistry effectively improves LGK974 solubility and bioavailability.
  • CD:LGK974 complexes offer a promising strategy for safer and repeated administration of Wnt signaling inhibitors.
  • These complexes hold significant potential for the treatment of various malignancies, including lung cancer.

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