PET Imaging of β-Glucuronidase Activity by an Activity-Based 124I-Trapping Probe for the Personalized Glucuronide Prodrug Targeted Therapy
| Autor: | Tian-Lu Cheng, Chih Hung Chuang, Yu Ling Leu, Ta Chun Cheng, Jaw-Yuan Wang, Kai Chuan Chen, Hsin Ell Wang, Steve R. Roffler, Chien Han Kao, Yu-Cheng Su |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Biodistribution medicine.medical_treatment Pharmacology Sensitivity and Specificity Targeted therapy Iodine Radioisotopes Mice Glucuronides In vivo Cell Line Tumor Neoplasms medicine Animals Humans Prodrugs Tissue Distribution Cytotoxicity Glucuronidase Chemistry Cancer Prodrug medicine.disease Xenograft Model Antitumor Assays Tumor Burden Disease Models Animal Oncology Cell culture Positron-Emission Tomography Female Glucuronide |
| Zdroj: | Molecular Cancer Therapeutics. 13:2852-2863 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-14-0212 |
| Popis: | 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 124I-tyramine–conjugated difluoromethylphenol beta-glucuronide probe (TrapG) to form 124I-TrapG that could be selectively activated by βG for subsequent attachment of 124I-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 124I-TrapG. βG targeting of 124I-TrapG in vivo was examined by micro-PET. The biodistribution of 131I-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. 124I-TrapG preferentially accumulated in CT26/mβG but not CT26 cells. Meanwhile, micro-PET and whole-body autoradiography results demonstrated that 124I-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. 124I-TrapG exhibited low cytotoxicity allowing long-term monitoring of βG activity in vivo to aid in the optimization of prodrug targeted therapy. Mol Cancer Ther; 13(12); 2852–63. ©2014 AACR. |
| Databáze: | OpenAIRE |
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