2'[(18)F]-fluoroethylrhodamine B is a promising radiotracer to measure P-glycoprotein function.

Abstract

In vivo detection of the emergence of P-glycoprotein (Pgp) mediated multidrug resistance in tumors could be beneficial for patients treated with anticancer drugs. PET technique in combination with appropriate radiotracers could be the most convenient method for detection of Pgp function. Rhodamine derivatives are validated fluorescent probes for measurement of mitochondrial membrane potential and also Pgp function. The aim of this study was to investigate whether 2'[(18)F]-fluoroethylrhodamine B ((18)FRB) a halogenated rhodamine derivative previously synthesized for PET assessment of myocardial perfusion preserved its Pgp substrate character. ATPase assay as well as accumulation experiments carried out using Pgp(+) and Pgp(-) human gynecologic (A2780/A2780(AD) and KB-3-1/KB-V1) and a mouse fibroblast cell pairs (NIH 3T3 and NIH 3T3 MDR1) were applied to study the interaction of (18)FRB with Pgp. ATPase assay proved that (18)FRB is a high affinity substrate of Pgp. Pgp(-) cells accumulated the (18)FRB rapidly in accordance with its lipophilic character. Dissipation of the mitochondrial proton gradient by a proton ionophore CCCP decreased the accumulation of rhodamine 123 (R123) and (18)FRB into Pgp(-) cells. Pgp(+) cells exhibited very low R123 and (18)FRB accumulation (around 1-8% of the Pgp(-) cell lines) which was not sensitive to the mitochondrial proton gradient; rather it was increased by the Pgp inhibitor cyclosporine A (CsA). Based on the above data we conclude that (18)FRB is a high affinity Pgp substrate and consequently a potential PET tracer to detect multidrug resistant tumors as well as the function of physiological barriers expressing Pgp.

• Authors: György Trencsényi, István Kertész, Zoárd T Krasznai, Gábor Máté, Gábor Szalóki, P Szabó Judit, Levente Kárpáti, Zoltán Krasznai, Teréz Márián, Katalin Goda
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 74 Pg. 27-35 (Jul 10 2015) ISSN: 1879-0720 [Electronic] Netherlands
• PMID: 25857708 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• 2'-fluoroethyl rhodamine B
• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Fluorescent Dyes
• Fluorine Radioisotopes
• Immunosuppressive Agents
• Neoplasm Proteins
• Proton Ionophores
• Radioactive Tracers
• Recombinant Proteins
• Rhodamines
• Rhodamine 123
• Cyclosporine

Topics

• ATP Binding Cassette Transporter, Subfamily B (antagonists & inhibitors, genetics, metabolism)
• Absorption, Physiological (drug effects)
• Animals
• Carcinoma (drug therapy, metabolism)
• Cell Line, Tumor
• Cyclosporine (pharmacology)
• Drug Resistance, Neoplasm
• Female
• Fluorescent Dyes (metabolism)
• Fluorine Radioisotopes
• Humans
• Immunosuppressive Agents (pharmacology)
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• NIH 3T3 Cells
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Ovarian Neoplasms (drug therapy, metabolism)
• Proton Ionophores (pharmacology)
• Radioactive Tracers
• Recombinant Proteins (chemistry, metabolism)
• Rhodamine 123 (metabolism)
• Rhodamines (metabolism)
• Uterine Cervical Neoplasms (drug therapy, metabolism)