Micro-PET Imaging of β-Glucuronidase Activity by the Hydrophobic Conversion of a Glucuronide Probe

Tzou, Shey-Cherng; Roffler, Steve R.; Chuang, Kuo-Hsiang; Yeh, Hsin-Pei; Kao, Chien-Han; Su, Yu-Cheng; Cheng, C. C.; Tseng, Wei‐Lung; Shiea, Jentaie; Harm, I-Hong; Cheng, Kai-Wen; Chen, Bing‐Mae; Hwang, Jeng-Jong; Cheng, Tian‐Lu; Wang, Hsin‐Ell

doi:10.1148/radiol.2523082055

Cited by 17 publications

(16 citation statements)

References 42 publications

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“…39 bG does accumulate in the interstitial space in tumors due to secretion by tumorinfiltrating monocytes and release from necrotic cancer cells. [42][43][44] This explains the effectiveness of cancer monotherapy with synthetic glucuronide prodrugs of Figure 4 Growth of tumors expressing membrane-bound b-glucuronidase (bG) was suppressed to a greater degree than parental tumors. Beige-Scid mice bearing 110-130 mm 3 subcutaneous tumors were intravenously injected with 10 mg kg À1 CPT-11 or PBS on two consecutive days (indicated as arrows).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of β–glucuronidase in tumors

Huang

Prijovich

et al. 2011

Cancer Gene Ther

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CPT-11 is a clinically important prodrug that requires conversion into the active metabolite SN-38, a potent topoisomerase I poison, for antitumor activity. However, SN-38 is rapidly metabolized to the inactive SN-38 glucuronide (SN-38G) in the liver, which reduces the amount of SN-38 available for killing cancer cells. Here, we investigated if local expression of b-glucuronidase (bG) on cancer cells to catalytically convert SN38G to SN38 could enhance the antitumor activity of CPT-11. bG was tethered on the plasma membrane of three different human cancer cell lines: human colon carcinoma (LS174T), lung adenocarcinoma (CL1-5) and bladder carcinoma (EJ). Surface b-glucuronidase-expressing cells were 20 to 80-fold more sensitive to SN-38G than the parental cells. Intravenous CPT-11 produced significantly greater suppression of CL1-5 and LS174 T tumors that expressed bG as compared with unmodified tumors. Furthermore, an adenoviral vector expressing membrane-tethered bG (Ad.bG) increased the sensitivity of cancer cells to SN-38G even at multiplicity of infections as low as 0.16, indicating bystander killing of non-transduced cancer cells. Importantly, intratumoral injection of Ad.bG significantly enhanced the in vivo antitumor activity of CPT-11 as compared with treatment with CPT-11 or Ad vectors alone. This study shows that Ad.bG has potential to boost the therapeutic index of CPT-11.

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Section: Discussionmentioning

confidence: 99%

Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of β–glucuronidase in tumors

Huang

Prijovich

et al. 2011

Cancer Gene Ther

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“…Compound 5 shown in Supplementary Methods (Tyramine-TrapG) was labeled with iodine 124 ( 124 I) NaI (3.7 -37 MBq; IBA Molecular) or 131 I NaI solution (Nuclear Science and Technology Development Center, National Tsing Hua University, Taiwan) using chloramine-T methods as previously described (3). The specific activity of 131 I-TrapG and 124 I-TrapG were about 500 MBq/mol with > 95% purity as determined by radio-thin-layer chromatography.…”

Section: Radioiodination Of 131 I or 124 I-trapgmentioning

confidence: 99%

“…It has been widely used as an attractive enzyme for reporter imaging (2)(3)(4) and cancer prodrug therapies (5)(6)(7)(8). Several glucuronide prodrugs have been used in antibody-directed enzyme prodrug therapy (ADEPT; refs.…”

mentioning

confidence: 99%

PET Imaging of β-Glucuronidase Activity by an Activity-Based 124I-Trapping Probe for the Personalized Glucuronide Prodrug Targeted Therapy

Cheng

Leu

et al. 2014

Molecular Cancer Therapeutics

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Beta-glucuronidase (bG) is a potential biomarker for cancer diagnosis and prodrug therapy. The ability to image bG activity in patients would assist in personalized glucuronide prodrug cancer therapy. However, whole-body imaging of bG activity for medical usage is not yet available. Here, we developed a radioactive bG 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 bG for subsequent attachment of 124 I-tyramine to nucleophilic moieties near bG-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. bG 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 bG activity and assessed its correlation with therapeutic efficacy of 9-aminocamptothecin glucuronide (9ACG) prodrug in native tumors. FITC-TrapG showed specific trapping at bG-expressing CT26 (CT26/mbG) cells but not in CT26 cells. The native TrapG probe possessed low cytotoxicity. 124 ITrapG preferentially accumulated in CT26/mbG but not CT26 cells. Meanwhile, micro-PET and wholebody autoradiography results demonstrated that 124 I-TrapG signals in CT26/mbG tumors were 141.4-fold greater than in CT26 tumors. Importantly, Colo205 xenografts in nude mice that express elevated endogenous bG 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 bG activity in vivo to aid in the optimization of prodrug targeted therapy.

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“…Female BALB/c nude mice (6-8 wk old) and female BALB/c mice (6-8 wk old) were obtained from the National Laboratory Animal Center, Taipei, Taiwan. All mice receiving radioiodinated probes were pretreated with Lugol solution (Sigma) in their drinking water for 2 d to block thyroidal uptake of free radioiodine (18). All animal experiments were performed in accordance with institutional guidelines and approved by the Animal Care and Use Committee of the Kaohsiung Medical University.…”

Section: Cells and Animalsmentioning

confidence: 99%

“…The mice were sequentially imaged at 4, 24, and 48 h after injection with a micro-PET R4 scanner (Concorde Microsystems), following an imaging protocol previously described (18).…”

Section: T2-weighted Mri Of Anti-peg Reporter In Vitro and In Vivomentioning

confidence: 99%

Development of a Universal Anti–Polyethylene Glycol Reporter Gene for Noninvasive Imaging of PEGylated Probes

Chuang¹,

Wang²,

Cheng³

et al. 2010

J Nucl Med

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Micro-PET Imaging of β-Glucuronidase Activity by the Hydrophobic Conversion of a Glucuronide Probe

Abstract: Hydrophilic-hydrophobic conversion of (124)I-PTH-G probe can aid in imaging of betaG-expressing tumors in vivo.

Cited by 17 publications

References 42 publications

Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of β–glucuronidase in tumors

Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of β–glucuronidase in tumors

PET Imaging of β-Glucuronidase Activity by an Activity-Based 124I-Trapping Probe for the Personalized Glucuronide Prodrug Targeted Therapy

Development of a Universal Anti–Polyethylene Glycol Reporter Gene for Noninvasive Imaging of PEGylated Probes

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