title: Evaluation of Near Infrared Dyes as Markers of P-Glycoprotein Activity in Tumors.
abstract: Aim:The multidrug resistance protein 1 (MDR1; P-glycoprotein) has been associated with eﬄux of chemotherapeutic agents from tumor cells and with poor patient prognosis. This study evaluated the feasibility of non-invasive, non-radioactive near infrared (NIR) imaging methodology for detection of MDR1 functional activity in tumors.Methods:Initial accumulation assays were conducted in MDR1-overexpressing MDCK cells (MDCK-MDR1) and control MDCK cells (MDCK-CT) using the NIR dyes indocyanine green (ICG), IR-783, IR-775, rhodamine 800, XenoLight DiR, and Genhance 750, at 0.4 μM-100 μM. ICG and IR-783 were also evaluated in HT-29 cells in which MDR1 overexpression was induced by colchicine (HT-29-MDR1) and their controls (HT-29-CT).In vivooptical imaging studies were conducted using immunodeficient mice bearing HT-29-CT and HT-29-MDR1 xenografts.Results:ICG's emission intensity was 2.0- and 2.2-fold higher in control versus MDR1-overexpressing cells, in MDCK and HT-29 cell lines, respectively. The respective IR-783 control:MDR1 ratio was 1.4 in both MDCK and HT-29 cells. Optical imaging of mice bearing HT-29-CT and HT-29-MDR1 xenografts revealed a statistically non-significant, 1.7-fold difference (p> 0.05) in ICG emission intensity between control and MDR1 tumors. No such differences were observed with IR-783.Conclusion:ICG and IR-783 appear to be weak MDR1 substrates.In vivo, low sensitivity and high between-subject variability impair the ability to use the currently studied probes as markers of tumor MDR1 activity. The results suggest that, for future use of this technology, additional NIR probes should be screened as MDR1 substrates.
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem Jerusalem, Israel.
authors.forename: Inessa
authors.initials: I
authors.lastname: Semenenko
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem Jerusalem, Israel.
authors.forename: Emma
authors.initials: E
authors.lastname: Portnoy
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem Jerusalem, Israel.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Aboukaoud
authors.affiliation: Department of Pharmacometrics, University of Maryland, College ParkMD, USA; Department of Pharmacometrics, University of Minnesota, MinneapolisMN, USA.
authors.forename: Serge
authors.initials: S
authors.lastname: Guzy
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem Jerusalem, Israel.
authors.forename: Miriam
authors.initials: M
authors.lastname: Shmuel
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem Jerusalem, Israel.
authors.forename: Gal
authors.initials: G
authors.lastname: Itzhak
authors.affiliation: Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem Jerusalem, Israel.
authors.forename: Sara
authors.initials: S
authors.lastname: Eyal
keywords: IR-783; MDR1; P-glycoprotein; cancer; indocyanine green; multidrug resistance; near infrared imaging