title: Imaging the DNA Alkylator Melphalan by CEST MRI: An Advanced Approach to Theranostics.
abstract: Brain tumors are among the most lethal types of tumors. Therapeutic response variability and failure in patients have been attributed to several factors, including inadequate drug delivery to tumors due to the blood-brain barrier (BBB). Consequently, drug delivery strategies are being developed for the local and targeted delivery of drugs to brain tumors. These drug delivery strategies could benefit from new approaches to monitor the delivery of drugs to tumors. Here, we evaluated the feasibility of imaging 4-[bis(2-chloroethyl)amino]-l-phenylalanine (melphalan), a clinically used DNA alkylating agent, using chemical exchange saturation transfer magnetic resonance imaging (CEST MRI), for theranostic applications. We evaluated the physicochemical parameters that affect melphalan's CEST contrast and demonstrated the feasibility of imaging the unmodified drug by saturating its exchangeable amine protons. Melphalan generated a CEST signal despite its reactivity in an aqueous milieu. The maximum CEST signal was observed at pH 6.2. This CEST contrast trend was then used to monitor therapeutic responses to melphalan in vitro. Upon cell death, the decrease in cellular pH from ∼7.4 to ∼6.4 caused an amplification of the melphalan CEST signal. This is contrary to what has been reported for other CEST contrast agents used for imaging cell death, where a decrease in the cellular pH following cell death results in a decrease in the CEST signal. Ultimately, this method could be used to noninvasively monitor melphalan delivery to brain tumors and also to validate therapeutic responses to melphalan clinically.
authors.affiliation: Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.|Cellular Imaging Section and Vascular Biology Program, Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Ethel J
authors.initials: EJ
authors.lastname: Ngen
authors.affiliation: Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.|Cellular Imaging Section and Vascular Biology Program, Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Amnon
authors.initials: A
authors.lastname: Bar-Shir
authors.affiliation: Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.|Cellular Imaging Section and Vascular Biology Program, Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Jablonska
authors.affiliation: Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.|F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute , Baltimore, Maryland 21205, United States.
authors.forename: Guanshu
authors.initials: G
authors.lastname: Liu
authors.affiliation: Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.|F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute , Baltimore, Maryland 21205, United States.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Song
authors.forename: Roxana
authors.initials: R
authors.lastname: Ansari
authors.affiliation: Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.|Cellular Imaging Section and Vascular Biology Program, Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.|F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute , Baltimore, Maryland 21205, United States.
authors.forename: Jeff W M
authors.initials: JW
authors.lastname: Bulte
authors.affiliation: Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.|Cellular Imaging Section and Vascular Biology Program, Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.|NeuroRepair Department, Mossakowski Medical Research Centre, PAS , 02106 Warsaw, Poland.|Department of Neurosurgery, Mossakowski Medical Research Centre, PAS , 02106 Warsaw, Poland.
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Janowski
authors.affiliation: Division of Interventional Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Sciences, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.|Department of Radiology, Children's National Medical Center , Washington, D.C. 20010, United States.
authors.forename: Monica
authors.initials: M
authors.lastname: Pearl
authors.affiliation: Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.|Cellular Imaging Section and Vascular Biology Program, Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.|Department of Radiology, Faculty of Medical Sciences, University of Warmia and Mazury , Olsztyn, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Walczak
authors.affiliation: Division of Magnetic Resonance Research, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.|Cellular Imaging Section and Vascular Biology Program, Institute for Cellular Engineering, The Johns Hopkins University School of Medicine , Baltimore, Maryland 21205, United States.|F. M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute , Baltimore, Maryland 21205, United States.
authors.forename: Assaf A
authors.initials: AA
authors.lastname: Gilad
mesh_terms: D000477:Alkylating Agents / Q000737:chemistry; D001812:Blood-Brain Barrier / Q000187:drug effects; D045744:Cell Line, Tumor; D003287:Contrast Media; D004247:DNA / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008558:Melphalan / Q000737:chemistry*
chemical_list: D000477:Alkylating Agents; D003287:Contrast Media; D004247:DNA; D008558:Melphalan
keywords: CEST; MRI; drug imaging; melphalan; theranostics; therapeutic response assessment