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

• Main Authors: Glaucio Valdameri (Author), Diogo Henrique Kita (Author), Julia de Paula Dutra (Author), Diego Lima Gomes (Author), Arun Kumar Tonduru (Author), Thales Kronenberger (Author), Bruno Gavinho (Author), Izadora Volpato Rossi (Author), Mariana Mazetto de Carvalho (Author), Basile Pérès (Author), Ingrid Fatima Zattoni (Author), Fabiane Gomes de Moraes Rego (Author), Geraldo Picheth (Author), Rilton Alves de Freitas (Author), Antti Poso (Author), Suresh V. Ambudkar (Author), Marcel I. Ramirez (Author), Ahcène Boumendjel (Author), Vivian Rotuno Moure (Author)
• Format: Book
• Published: MDPI AG, 2023-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 <b>4a</b> (<b>C4a</b>). Molecular docking and in vitro assays using ABCG2 and P-glycoprotein (P-gp) expressing membrane vesicles of insect cells revealed that <b>C4a</b> interacts with both transporters, while showing selectivity toward ABCG2 using cell-based transport assays. <b>C4a</b> inhibited the ABCG2-mediated efflux of different substrates and molecular dynamic simulations demonstrated that <b>C4a</b> binds in the Ko143-binding pocket. Liposomes and extracellular vesicles (EVs) of <i>Giardia intestinalis</i> and human blood were used to successfully bypass the poor water solubility and delivery of <b>C4a</b> 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.

Item Description

10.3390/pharmaceutics15041259
1999-4923