2. Academic Validation
  3. Synthesis and Evaluation of Radiolabeled Phosphoramide Mustard with Selectivity for Hypoxic Cancer Cells

Synthesis and Evaluation of Radiolabeled Phosphoramide Mustard with Selectivity for Hypoxic Cancer Cells

  • ACS Med Chem Lett. 2017 Oct 23;8(12):1269-1274. doi: 10.1021/acsmedchemlett.7b00355.
Wenting Zhang 1 2,  Wei Fan 1 2,  Zhengyuan Zhou 3,  Jered Garrison 1 4 2 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
  • 2 Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
  • 3 Department of Radiology, Duke University Medical Center, Durham, North Carolina 27710, United States.
  • 4 Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
  • 5 Eppley Cancer Center, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, Nebraska 68198, United States.
PMID: 29259746 DOI: 10.1021/acsmedchemlett.7b00355
Abstract

Tumor hypoxia has been widely explored over the years as a diagnostic and therapeutic marker. Herein, we synthesized an alkyne functionalized version of evofosfamide, a hypoxia-selective prodrug. The purpose of this effort was to investigate if this novel 2-nitroimidazole phosphoramide nitrogen mustard (2-NIPAM) retained hypoxia selectivity and could be utilized in radiopharmaceutical development to significantly increase retention of conjugated agents in hypoxic cells. 2-NIPAM demonstrated good hypoxia selectivity with a 62- and 225-fold increase in cytotoxicity toward PC-3 and DU145 human prostate Cancer cell lines, respectively, under hypoxic conditions. Radiolabeling of 2-NIPAM with 125I was accomplished through a Cu(I)-mediated azide-alkyne cycloaddition reaction. The 125I-conjugate demonstrated 13.6 and 17.8% lower efflux rates for DU145 and PC-3 cells, correspondingly, under hypoxic conditions, suggesting that the increased retention is likely due to the known intracellular trapping mechanism. In conclusion, these studies demonstrate the potential of 2-NIPAM in serving as a trapping agent for radiopharmaceutical development.

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