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

• Published in: Pharmaceutics Vol. 15; no. 4; p. 1259
• Main Authors: Valdameri, Glaucio, Kita, Diogo Henrique, Dutra, Julia de Paula, Gomes, Diego Lima, Tonduru, Arun Kumar, Kronenberger, Thales, Gavinho, Bruno, Rossi, Izadora Volpato, Carvalho, Mariana Mazetto de, Pérès, Basile, Zattoni, Ingrid Fatima, Rego, Fabiane Gomes de Moraes, Picheth, Geraldo, Freitas, Rilton Alves de, Poso, Antti, Ambudkar, Suresh V, Ramirez, Marcel I, Boumendjel, Ahcène, Moure, Vivian Rotuno
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.04.2023; MDPI
• Subjects: ABC transporters; ABCG2 transporter; Apoptosis; Cancer; Cancer therapies; Care and treatment; Carrier proteins; Cells; chromones; Clinical trials; Dosage and administration; drug delivery; Drug delivery systems; Drug resistance; Drugs; Evaluation; Extracellular vesicles; Flow cytometry; Identification and classification; inhibitors; Microscopy; Physiology; Potassium; Proteins; Structure; Tumors; Vehicles; Brazil; United States > US; inhibitors; ABCG2 transporter; extracellular vesicles; drug delivery; chromones
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics15041259

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