PET imaging of β-glucuronidase activity by an activity-based 124I-trapping probe for the personalized glucuronide prodrug targeted therapy.

Beta-glucuronidase (βG) is a potential biomarker for cancer diagnosis and prodrug therapy. The ability to image βG activity in patients would assist in personalized glucuronide prodrug cancer therapy. However, whole-body imaging of βG activity for medical usage is not yet available. Here, we developed a radioactive βG activity-based trapping probe for positron emission tomography (PET). We generated a (124)I-tyramine-conjugated difluoromethylphenol beta-glucuronide probe (TrapG) to form (124)I-TrapG that could be selectively activated by βG for subsequent attachment of (124)I-tyramine to nucleophilic moieties near βG-expressing sites. We estimated the specificity of a fluorescent FITC-TrapG, the cytotoxicity of tyramine-TrapG, and the serum half-life of (124)I-TrapG. βG targeting of (124)I-TrapG in vivo was examined by micro-PET. The biodistribution of (131)I-TrapG was investigated in different organs. Finally, we imaged the endogenous βG activity and assessed its correlation with therapeutic efficacy of 9-aminocamptothecin glucuronide (9ACG) prodrug in native tumors. FITC-TrapG showed specific trapping at βG-expressing CT26 (CT26/mβG) cells but not in CT26 cells. The native TrapG probe possessed low cytotoxicity. (124)I-TrapG preferentially accumulated in CT26/mβG but not CT26 cells. Meanwhile, micro-PET and whole-body autoradiography results demonstrated that (124)I-TrapG signals in CT26/mβG tumors were 141.4-fold greater than in CT26 tumors. Importantly, Colo205 xenografts in nude mice that express elevated endogenous βG can be monitored by using infrared glucuronide trapping probes (NIR-TrapG) and suppressed by 9ACG prodrug treatment. (124)I-TrapG exhibited low cytotoxicity allowing long-term monitoring of βG activity in vivo to aid in the optimization of prodrug targeted therapy.
AuthorsYu-Cheng Su, Ta-Chun Cheng, Yu-Ling Leu, Steve R Roffler, Jaw-Yuan Wang, Chih-Hung Chuang, Chien-Han Kao, Kai-Chuan Chen, Hsin-Ell Wang, Tian-Lu Cheng
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 12 Pg. 2852-63 (Dec 2014) ISSN: 1538-8514 [Electronic] United States
PMID25277385 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright©2014 American Association for Cancer Research.
Chemical References
  • Glucuronides
  • Iodine Radioisotopes
  • Prodrugs
  • Glucuronidase
  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Glucuronidase (metabolism)
  • Glucuronides (therapeutic use)
  • Humans
  • Iodine Radioisotopes
  • Mice
  • Neoplasms (diagnosis, drug therapy, metabolism)
  • Positron-Emission Tomography (methods)
  • Prodrugs
  • Sensitivity and Specificity
  • Tissue Distribution
  • Tumor Burden (drug effects)
  • Xenograft Model Antitumor Assays

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