Abstract |
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.
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Authors | Yu-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 |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 13
Issue 12
Pg. 2852-63
(Dec 2014)
ISSN: 1538-8514 [Electronic] United States |
PMID | 25277385
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | ©2014 American Association for Cancer Research. |
Chemical References |
- Glucuronides
- Iodine Radioisotopes
- Prodrugs
- Glucuronidase
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Topics |
- 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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