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Conjugated Proteins02:50

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Real-time Measurement of Epithelial Barrier Permeability in Human Intestinal Organoids
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GM1-Binding Conjugates To Improve Intestinal Permeability.

Alexandre Melkoumov1, Isabelle St-Jean1, Xavier Banquy1

  • 1Faculty of Pharmacy , Université de Montréal , H3C 3J7 Montréal , Québec , Canada.

Molecular Pharmaceutics
|November 14, 2018
PubMed
Summary
This summary is machine-generated.

Cholera toxin β subunit (CTB) and GM1-binding peptides were explored as carriers to improve oral drug delivery. CTB enhanced the uptake of macromolecules via a GM1-dependent pathway, showing potential for improving oral bioavailability.

Keywords:
GM1bioconjugatescholera toxinintestinal permeabilityoral bioavailabilitypeptide conjugate

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Area of Science:

  • Pharmacology
  • Biotechnology
  • Drug Delivery

Background:

  • Poor intestinal permeability limits oral bioavailability of many drugs and proteins.
  • Receptor-mediated endocytosis and transcytosis offer strategies to overcome intestinal barriers.
  • Cholera toxin β subunit (CTB) binds to intestinal receptor GM1, enabling barrier crossing.

Purpose of the Study:

  • To evaluate GM1-binding peptides and CTB as covalent carriers for poorly permeable molecules.
  • To assess the efficacy of these carriers in enhancing cellular internalization and intestinal permeability.
  • To investigate the role of GM1 receptor interactions in the transport mechanism.

Main Methods:

  • Conjugation of model drugs (fluorescent probes, albumin-FITC) to GM1-binding peptides (G23, P3) and CTB using click chemistry.
  • Affinity assessment of conjugates with GM1 receptor using isothermal titration calorimetry and microscale thermophoresis.
  • Evaluation of cellular internalization in Caco-2 and T84 cells and permeability across cell monolayers.

Main Results:

  • Peptide conjugates showed improved internalization into Caco-2 and T84 cells, independent of GM1 receptor levels.
  • CTB conjugates significantly increased cellular internalization of albumin-FITC in a GM1-dependent manner.
  • Peptide conjugates had limited permeability, while G23 and CTB conjugates slightly enhanced permeability in T84 cells.

Conclusions:

  • CTB serves as a promising carrier for enhancing the oral bioavailability of macromolecules like albumin, heparins, proteins, and siRNAs.
  • GM1-binding peptides offer potential for drug internalization but show limited impact on intestinal permeability.
  • The GM1-dependent pathway mediated by CTB is a key mechanism for improving oral delivery of large molecules.