Characterization of Potent ABCG2 Inhibitor Derived from Chromone: From the Mechanism of Inhibition to Human Extracellular Vesicles for Drug Delivery - Université Grenoble Alpes
Article Dans Une Revue Pharmaceutics Année : 2023

Characterization of Potent ABCG2 Inhibitor Derived from Chromone: From the Mechanism of Inhibition to Human Extracellular Vesicles for Drug Delivery

Glaucio Valdameri
Diogo Henrique Kita
  • Fonction : Auteur
Julia de Paula Dutra
  • Fonction : Auteur
Diego Lima Gomes
  • Fonction : Auteur
Arun Kumar Tonduru
Thales Kronenberger
Bruno Gavinho
  • Fonction : Auteur
Izadora Volpato Rossi
Mariana Mazetto De Carvalho
  • Fonction : Auteur
Basile Pérès
  • Fonction : Auteur
Ingrid Fatima Zattoni
  • Fonction : Auteur
Fabiane Gomes de Moraes Rego
  • Fonction : Auteur
Geraldo Picheth
  • Fonction : Auteur
Rilton Alves De Freitas
  • Fonction : Auteur
Antti Poso
Suresh Ambudkar
Marcel Ramirez
  • Fonction : Auteur
Ahcène Boumendjel
Vivian Rotuno Moure
  • Fonction : Auteur

Résumé

Inhibition of ABC transporters is a promising approach to overcome multidrug resistance in cancer. Herein, we report the characterization of a potent ABCG2 inhibitor, namely, chromone 4a (C4a). Molecular docking and in vitro assays using ABCG2 and P-glycoprotein (P-gp) expressing membrane vesicles of insect cells revealed that C4a interacts with both transporters, while showing selectivity toward ABCG2 using cell-based transport assays. C4a inhibited the ABCG2-mediated efflux of different substrates and molecular dynamic simulations demonstrated that C4a binds in the Ko143-binding pocket. Liposomes and extracellular vesicles (EVs) of Giardia intestinalis and human blood were used to successfully bypass the poor water solubility and delivery of C4a as assessed by inhibition of the ABCG2 function. Human blood EVs also promoted delivery of the well-known P-gp inhibitor, elacridar. Here, for the first time, we demonstrated the potential use of plasma circulating EVs for drug delivery of hydrophobic drugs targeting membrane proteins.

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Chimie

Dates et versions

hal-04774413 , version 1 (08-11-2024)

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Citer

Glaucio Valdameri, Diogo Henrique Kita, Julia de Paula Dutra, Diego Lima Gomes, Arun Kumar Tonduru, et al.. Characterization of Potent ABCG2 Inhibitor Derived from Chromone: From the Mechanism of Inhibition to Human Extracellular Vesicles for Drug Delivery. Pharmaceutics, 2023, 15 (4), pp.1259. ⟨10.3390/pharmaceutics15041259⟩. ⟨hal-04774413⟩

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