Imaging the DNA alkylator melphalan by CEST MRI: An advanced approach to theranostics

Ethel J. Ngen, Amnon Bar-Shir, Anna Jablonska, Guanshu Liu, Xiaolei Song, Roxana Ansari, Jeff W.M. Bulte, Miroslaw Janowski, Monica Pearl, Piotr Walczak, Assaf A. Gilad

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3043-3053
Number of pages11
JournalMolecular Pharmaceutics
Issue number9
StatePublished - Sep 6 2016


  • CEST
  • MRI
  • drug imaging
  • melphalan
  • theranostics
  • therapeutic response assessment

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery


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