PubMed Health⌕ Search

Biomedical subjects

David J Yang

Publications and source records attributed to David J Yang.

15 recordsLinked to original sources
PubMed2007

Infrared-based module for the synthesis of 68Ga-labeled radiotracers.

INTRODUCTION: Generator-produced positron emission tomography tracers have gained much attention recently due to favorable imaging characteristics, accessibility and affordability. The focus of this study was to design and validate a semiautomated module for 68Ga-labeled chemistry utilizing infrared-based heating for rapid control of thermal cycle. METHODS: A prototype module was built and installed in our laboratory. DOTA (1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetra-acetic acid) was manually labeled (10-1000 nmol) with 68Ga to optimize synthesis conditions. For automation, 250 nmol of DOTA was labeled with 68Ga with reaction times of 5 min (n=5), 10 min (n=5) and 20 min (n=6). A dose calibrator and radio-thin-layer chromatography were used to access the product yield and quality of both manual and automated syntheses. RESULTS: A semiautomated 68Ga synthesis module was developed. The system showed that software control could be used to drive a multistep radiochemical synthesis and to produce 68Ga-DOTA with >95% radiochemical purity, similar to that in manual synthesis. The device also showed that for a short reaction time of 5 min, decay-corrected radioactive yields of >70% could be achieved. The total synthesis was as short as 22 min, including 6-8 min for HCl evaporation. The temperature and pressure profiles of the process were consistent. CONCLUSION: We demonstrated the use of a commercially available 68Ga/68Ge generator with a semiautomated module to successfully label the bifunctional chelator DOTA with 68Ga. Further investigation with different 68Ga-labeled bioconjugates is warranted to demonstrate the usefulness of the module as a tool for tracer development and imaging research.

Chemistry, Pharmaceutical↗
PubMed2006

Targeted functional imaging of estrogen receptors with 99mTc-GAP-EDL.

PURPOSE: To evaluate the feasibility of using (99m)Tc-glutamate peptide-estradiol in functional imaging of estrogen receptor-positive [ER(+)] diseases. METHODS: 3-Aminoethyl estradiol (EDL) was conjugated to glutamate peptide (GAP) to yield GAP-EDL. Cellular uptake studies of (99m)Tc-GAP-EDL were conducted in ER(+) cell lines (MCF-7, 13762 and T47D). To demonstrate whether GAP-EDL increases MAP kinase activation, Western blot analysis of GAP-EDL was performed in 13762 cells. Biodistribution was conducted in nine rats with 13762 breast tumors at 0.5-4 h. Each rat was administered (99m)Tc-GAP-EDL. Two animal models (rats and rabbits) were created to ascertain whether tumor uptake of (99m)Tc-GAP-EDL was via an ER-mediated process. In the tumor model, breast tumor-bearing rats were pretreated with diethylstilbestrol (DES) 1 h prior to receiving (99m)Tc-GAP-EDL. In the endometriosis model, part of the rabbit uterine tissue was dissected and grafted to the peritoneal wall. The rabbit was administered with (99m)Tc-GAP-EDL. RESULTS: There was a 10-40% reduction in uptake of (99m)Tc-GAP-EDL in cells treated with DES or tamoxifen compared with untreated cells. Western blot analysis showed an ERK1/2 phosphorylation process with GAP-EDL. Biodistribution studies showed that tumor uptake and tumor-to-muscle count density ratio in (99m)Tc-GAP-EDL groups were significantly higher than those in (99m)Tc-GAP groups at 4 h. Among (99m)Tc-GAP-EDL groups, region of interest analysis of images showed that tumor-to muscle ratios were decreased in blocking groups. In the endometriosis model, the grafted uterine tissue could be visualized by (99m)Tc-GAP-EDL. CONCLUSION: Cellular or tumor uptake of (99m)Tc-GAP-EDL occurs via an ER-mediated process. (99m)Tc-GAP-EDL is a useful agent for imaging functional ER(+) disease.

Animals↗
PubMed2006

Targeted molecular imaging in oncology.

Improvement of scintigraphic tumor imaging is extensively determined by the development of more tumor specific radiopharmaceuticals. Thus, to improve the differential diagnosis, prognosis, planning and monitoring of cancer treatment, several functional pharmaceuticals have been developed. Application of molecular targets for cancer imaging, therapy and prevention using generator-produced isotopes is the major focus of ongoing research projects. Radionuclide imaging modalities (positron emission tomography, PET; single photon emission computed tomography, SPECT) are diagnostic cross-sectional imaging techniques that map the location and concentration of radionuclide-labeled radiotracers. 99mTc- and 68Ga-labeled agents using ethylenedicysteine (EC) as a chelator were synthesized and their potential uses to assess tumor targets were evaluated. 99mTc (t1/2 = 6 hr, 140 keV) is used for SPECT and 68Ga (t1/2 = 68 min, 511 keV) for PET. Molecular targets labeled with Tc-99m and Ga-68 can be utilized for prediction of therapeutic response, monitoring tumor response to treatment and differential diagnosis. Molecular targets for oncological research in (1) cell apoptosis, (2) gene and nucleic acid-based approach, (3) angiogenesis (4) tumor hypoxia, and (5) metabolic imaging are discussed. Numerous imaging ligands in these categories have been developed and evaluated in animals and humans. Molecular targets were imaged and their potential to redirect optimal cancer diagnosis and therapeutics were demonstrated.

Drug Delivery Systems↗
PubMed2006

PET and planar imaging of tumor hypoxia with labeled metronidazole.

RATIONALE AND OBJECTIVES: This study was aimed to develop 99mTc- and 68Ga-labeled metronidazole (MN) using ethylenedicysteine (EC) as a chelator and evaluate their potential use to assess tumor hypoxia. MATERIALS AND METHODS: EC-MN was labeled with 99mTc in the presence of tin (II) chloride. Labeling EC-MN with 68Ga was achieved by adding 68GaCl3 (2 mCi with 3.4 microg cold GaCl3). In vitro cellular uptakes of 99mTc- and 68Ga-EC-MN were obtained in various types of tumor cells at 0.5-4 hours. Tissue distribution and PET imaging of 99mTc and 68Ga-EC-MN were evaluated in breast tumor-bearing rats at 0.5-4 hours. Tumor oxygen tension was measured using an oxygen probe. RESULTS: There were similar cellular uptakes (2-10%) between 99mTc- and 68Ga-EC-MN at 0.5-4 hours. In vivo biodistribution of 99mTc- and 68Ga-EC-MN in breast tumor-bearing rats showed increased tumor-to-blood and tumor-to-muscle count density ratios as a function of time. Positron emission tomography images confirmed that the tumors could be visualized clearly with 68Ga-EC-MN. Oxygen tension in tumor tissue was determined to be 6-10 mm Hg compared with 40-50 mm Hg in normal muscle tissue. CONCLUSIONS: The results indicated that it is feasible to use 99mTc- and 68Ga-EC-MN for assessment of tumor hypoxia. These agents may be useful in selecting and evaluating cancer therapy.

Animals↗
PubMed2006

Radiolabeled L-lysine for tumor imaging.

RATIONALE AND OBJECTIVES: The aims of this study were to label the versatile amino acid l-lysine with (99m)Tc using 2,3-dimercapto-succinic acid (DMSA) as a chelator, and to assess its tumor imaging feasibility under in vivo and in vitro conditions, and finally to determine the subcellular biodistribution of this radiopharmaceutical. MATERIALS AND METHODS: DMSA-l-lysine was chemically synthesized and labeled with sodium pertechnetate. Nuclear magnetic resonance (NMR) and mass spectral analysis of DMSA-l-lysine were conducted. Radiochemical purity was determined by thin-layer chromatography (TLC) and paper chromatography. Cellular uptake, competition and subcellular localization studies were performed in rat breast cancer cells (13762). In vivo studies of planar imaging and biodistribution studies were performed on female Fischer 344 rats. Medical Internal Radiation Dose (MIRD) dosimetry estimates were calculated. RESULTS: Radiochemical purity (determined by radio-TLC and high-performance liquid chromatography) of these compounds was >95%. (99m)Tc-DMSA-l-lysine showed good uptake in in vitro cell culture assays and uptake was reduced in competition studies. (99m)Tc-DMSA-l-lysine accumulates in the nucleus as much as in the cytoplasm and it was also shown that accumulation of the (99m)Tc-DMSA-l-lysine in the nucleus increases as a function of a time. There was an increase in tumor-to-blood and tumor-to-muscle count density ratios. Tumor/background ratios were 5.75 at 1 hour and 6.87 at 2 hours. In vivo tissue distribution studies revealed that radiation dosimetry of blood-forming organs were within radiation dose limits. CONCLUSION: DMSA-l-lysine kits can be labeled with (99m)Tc easily and efficiently, with high radiochemical purity and cost-effectiveness. In vitro cellular uptake and scintigraphic imaging studies demonstrated the pharmacokinetic distribution and feasibility of using (99m)Tc-DMSA-l-lysine for tumor imaging.

Adenocarcinoma↗
PubMed2005

(99m)Tc-EC-guanine: synthesis, biodistribution, and tumor imaging in animals.

PURPOSE: DNA markers are useful in assessing cell proliferation. The purpose of this study was to synthesize (99m)Tc-ethylenedicysteine-guanine (EC-Guan) for evaluation of cell proliferation. METHODS: Tumor cells were incubated with (99m)Tc-EC-Guan for cell cycle analysis. Prostate tumor cells that were overexpressing the HSV thymidine kinase gene, or various tumor cells were incubated with (99m)Tc-EC-Guan at 0.5-2 h. Thymidine incorporation assays were performed in lung cancer cells incubated with EC-Guan at 0.1-1 mg/well. Tissue distribution, autoradiography, and planar scintigraphy of (99m)Tc-EC-Guan and (99m)Tc-EC (control) were determined in tumor-bearing rodents at 0.5-4 h. RESULTS: Cell culture assays indicated that EC-Guan was incorporated in DNA, and there was no significant uptake difference between HSVTK overexpressed and normal groups. Biodistribution and scintigraphic imaging studies of (99m)Tc-EC-Guan showed increased tumor/tissue count density ratios as a function of time. CONCLUSIONS: Our results indicate that (99m)Tc-EC-Guan may be useful as a tumor proliferation imaging agent.

Animals↗
PubMed2005

Regional radiochemotherapy using in situ hydrogel.

PURPOSE: To evaluate the feasibility of regional radiochemotherapy of mammary tumors using in situ hydrogel loaded with cisplatin (CDDP) and rhenium-188 ((188)Re). METHODS: Sodium alginate (SA) and calcium chloride were used to create a hydrogel for delivery of CDDP and (188)Re. In vitro studies were performed to evaluate cytotoxic effects of (188)Re-hydrogel and sustained-release ability of the CDDP-hydrogel. Tumor-bearing rats were injected with (188)Re-hydrogel (0.5-1 mCi/rat), (188)Re-perrhenate (0.5-1 mCi/rat, intratumoral, I.T.), CDDP-hydrogel (3 mg/kg), and (188)Re-hydrogel loaded with CDDP (3 mg/kg body weight, 0.5-1 mCi/rat), respectively, and groups receiving (188)Re were imaged at 24 and 48 h postinjection. Tumor volume, body weight, imaging, and kidney function were assessed as required for each group. RESULTS: Successful formation of the hydrogel was demonstrated by cytotoxic effects of (188)Re-hydrogel and slow release of CDDP-hydrogel in vitro. Tumor volume measurements showed significant delay in tumor growth in treated vs. control groups with minimal variation in normal kidney function for the CDDP-hydrogel group. Scintigraphic images indicated localization of (188)Re-hydrogel in the tumor site up to 48 h postinjection. CONCLUSIONS: Our data demonstrate the feasibility of using hydrogel for delivery of chemotherapeutics and radiation locally. This technique may have applications involving other contrast modalities as well as treatment in cases where tumors are inoperable.

Animals↗
PubMed2004

Assessment of cyclooxygense-2 expression with 99mTc-labeled celebrex.

Cyclooxygenase-2 (COX-2) plays an important role in angiogenesis and cancer progression. Since many tumor cells exhibit COX-2 expression, functional imaging of COX-2 expression using celebrex (CBX, a COX-2 inhibitor) may provide not only a non-invasive, reproducible, quantifiable alternative to biopsies, but it also greatly complements pharmacokinetic studies by correlating clinical responses with biological effects. Moreover, molecular endpoints of anti-COX-2 therapy could also be assessed effectively. This study aimed at measuring uptake of Tc-EC-CBX in COX-2 expression in tumor-bearing animal models. In vitro Western blot analysis and cellular uptake assays were used to examine the feasibility of using Tc-EC-CBX to measure COX-2 activity. Tissue distribution studies of Tc-EC-CBX were evaluated in tumor-bearing rodents at 0.5-4 h. Dosimetric absorption was then estimated. Planar scintigraphy was performed in mice, rats and rabbits bearing tumors. In vitro cellular uptake indicated that cells with higher COX-2 expression (A549 and 13762) had higher uptake of Tc-EC-CBX than lower COX-2 expression (H226). In vivo biodistribution of Tc-EC-CBX in tumor-bearing rodents showed increased tumor:tissue ratios as a function of time. In vitro and biodistribution studies demonstrated the possibility of using Tc-EC-CBX to assess COX-2 expression. Planar images confirmed that the tumors could be visualized with Tc-EC-CBX from 0.5 to 4 h in tumor-bearing animal models. We conclude that Tc-EC-CBX may be useful to assess tumor COX-2 expression. This may be useful in the future for selecting patients for treatment with anti-COX-2 agents.

Animals↗
PubMed2004

Radiation dosimetry of 99mTc-labeled C225 in patients with squamous cell carcinoma of the head and neck.

UNLABELLED: This study assessed the radiation dosimetry of 99mTc-labeled ethylene dicysteine (EC) C225 (EC-C225), a promising radioligand for functional tumor imaging. METHODS: Whole-body scanning was performed on 6 patients with head and neck squamous cell carcinoma up to 24 h after administration of 99mTc-EC-C225. Alternate patients who had been randomized to receive C225 in a phase III trial received 99mTc-EC-C225 before their 20-mg test dose or after their 400 mg/m2 loading dose of unlabeled C225 (patients 1/3/5 and 2/4/6, respectively). Radiation dosimetry was assessed using the MIRD method. RESULTS: The critical organ was the kidney, with an average radiation-absorbed dose for all 6 patients of 0.0274 mGy/MBq. The average total-body absorbed dose was 0.0022 mGy/MBq (0.243 cGy/1,110 MBq). CONCLUSION: The new radiopharmaceutical 99mTc-EC-C225 appears to have reasonable dosimetric properties for a diagnostic nuclear medicine agent. Correlation of the imaging results with clinical findings is the next step.

Antibodies, Monoclonal↗
PubMed2003

Prognostication of recovery in patients with acute ischemic stroke through the use of brain SPECT with Technetium-99m--labeled metronidazole.

BACKGROUND AND PURPOSE: We hypothesized that technetium-99m-ethylene dicysteine-metronidazole (99mTc-EC-MN) localizes to brain tissue that is hypoxic but viable. This study prospectively evaluated the relationship between neurological outcome and uptake of 99mTc-EC-MN in peri-infarcted regions of the brain. METHODS: Eight patients with acute ischemic stroke in the territory of the left middle cerebral artery underwent 99mTc-EC-MN and 99mTc-ethyl cysteinate dimer (ECD) brain SPECTs on the same day during the subacute stage (10.3+/-2.5 days). The infarct volumes from 99mTc-ECD images (IV(ECD)), infarct volumes from diffusion-weighted MRI images (IV(DW)), and hypoxic volume (HV) from 99mTc-EC-MN images were calculated. The net infarct volume (NIV(ECD)) was defined as IV(ECD) minus HV. The National Institutes of Health Stroke Scale scores were measured on admission and days 1, 3, 7, and 30. RESULTS: IV(ECD) was greater than IV(DW). The lesion-to-normal count-density ratios of 99mTc-EC-MN ranged from 1.80 to 5.96. HV was 60.2+/-65.2 cm3, and the mean percent HV was 24.5+/-28.1% of IV(ECD). NIV(ECD) was 162.6+/-133.4 cm3 and was significantly smaller than IV(ECD). NIV(ECD) was significantly correlated with National Institutes of Health Stroke Scale score at 1 month and was a significant predictor of neurological deficit at 1 month. CONCLUSIONS: 99mTc-EC-MN brain SPECT can detect hypoxic tissue after acute ischemic stroke and, in combination with 99mTc-ECD brain SPECT, is useful in predicting neurological outcome in ischemic stroke patients.

Acute Disease↗
PubMed2003

Assessment of epidermal growth factor receptor with 99mTc-ethylenedicysteine-C225 monoclonal antibody.

Epidermal growth factor receptor (EGFR) plays an important role in cell division and cancer progression, as well as angiogenesis and metastasis. Since many tumor cells exhibit the EGFR on their surface, functional imaging of EGFR provides not only a non-invasive, reproducible, quantifiable alternative to biopsies, but it also greatly complements pharmacokinetic studies by correlating clinical responses with biological effects. Moreover, molecular endpoints of anti-EGFR therapy could be assessed effectively. C225 is a chimeric monoclonal antibody that targets the human extracellular EGFR and inhibits the growth of EGFR-expressing tumor cells. Also, it has been demonstrated that C225, in combination with chemotherapeutic drugs or radiotherapy, is effective in eradicating well-established tumors in nude mice. We have developed 99mTc-labeled C225 using ethylenedicysteine (EC) as a chelator. This study aimed at measuring uptake of 99mTc-EC-C225 in EGFR+ tumor-bearing animal models and preliminary feasibility of imaging patients with head and neck carcinomas. In vitro Western blot analysis and cytotoxicity assays were used to examine the integrity of EC-C225. Tissue distribution studies of 99mTc-EC-C225 were evaluated in tumor-bearing rodents at 0.5-4 h. In vivo biodistribution of 99mTc-EC-C225 in tumor-bearing rodents showed increased tumor-to-tissue ratios as a function of time. In vitro and biodistribution studies demonstrated the possibility of using 99mTc-EC-C225 to assess EGFR expression. SPECT images confirmed that the tumors could be visualized with 99mTc-EC-C225 from 0.5 to 4 h in tumor bearing rodents. We conclude that 99mTc-EC-C225 may be useful to assess tumor EGFR expression. This may be useful in the future for selecting patients for treatment with C225.

Animals↗
PubMed2003

Imaging with 99mTc ECDG targeted at the multifunctional glucose transport system: feasibility study with rodents.

PURPOSE: To evaluate the feasibility of technetium 99m ((99m)Tc) ethylenedicysteine-deoxyglucose (ECDG) imaging in tumor-bearing rodents. MATERIALS AND METHODS: ECDG was synthesized by means of reacting ethylenedicysteine with glucosamine, with carbodiimide as the coupling agent. Hexokinase assays were performed at an ultraviolet wavelength of 340 nm. To determine whether blood glucose level could be altered, ECDG or glucosamine was injected into six rats. In a separate study, ECDG followed by insulin was administered to three rats. To determine biodistribution, lung tumor cells were intramuscularly injected into the hind legs of 18 nude mice. The animals were then injected with (99m)Tc ECDG or fluorine 18 ((18)F) fluorodeoxyglucose (FDG) (0.037-0.074 MBq per mouse). Radioactivity was measured in tissue excised from the animals. Scintigraphy was performed in three groups: in group 1 to demonstrate that different-sized tumors could be imaged after (99m)Tc ECDG administration, in group 2 to ascertain whether tumor uptake of (99m)Tc ECDG was perfusion related, and in group 3 to demonstrate that tumor uptake of (99m)Tc ECDG occurred by means of a glucose-mediated process. RESULTS: ECDG was positive for phosphorylation at hexokinase assay. Blood glucose level increased with ECDG injection and decreased with insulin administration. Tumor-to-brain tissue and tumor-to-muscle tissue ratios of (99m)Tc ECDG uptake were higher than those of (18)F FDG uptake. Scintigraphic results demonstrated the feasibility of (99m)Tc ECDG imaging. CONCLUSION: There are similarities between (99m)Tc ECDG uptake and (18)F FDG uptake in tumors, and study findings supported the potential use of (99m)Tc ECDG as a functional imaging agent.

Animals↗
PubMed2002

Assessment of antiangiogenic effect using 99mTc-EC-endostatin.

PURPOSE: Tumor vascular density may provide a prognostic indicator of metastatic potential or survival. The purpose of this study was to develop 99mTc-ethylenedicysteine-endostatin (99mTc-EC-endostatin) for the evaluation of anti-angiogenesis therapy. METHOD: 99mTc-EC-endostatin was prepared by conjugating ethylenedicysteine (EC) to endostatin, followed by adding pertechnetate and tin chloride. Radiochemical purity was > 95%. In vitro cell viability, affinity and TUNEL assays were performed. Tissue distribution and planar imaging of radiolabeled endostatin were determined in tumor-bearing rats. To assess anti-angiogenic treatment response, rats were treated with endostatin, paclitaxel and saline, followed by imaging with 99mTc-EC-endostatin. Tumor response to endostatin therapy in tumor-bearing animal models was assessed by correlating tumor uptake dose with microvessel density, VEGF, bFGF and IL-8 expression during endostatin therapy. RESULTS: In vitro cell viability and TUNEL assays indicated no marked difference between EC-endostatin and endostatin. Cellular uptake assay suggests that endostatin binds to endostatin receptor. Biodistribution of 99mTc-EC-endostatin in tumor-bearing rats showed increased tumor-to-tissue count density ratios as a function of time. Tumor uptake (%ID/g) of 99mTc-EC-endostatin was 0.2-0.5. Planar images confirmed that the tumors could be visualized clearly with 99mTc-EC-endostatin. The optimal time for imaging using radiolabeled endostatin was 2 hrs. 99mTc-EC-endostatin could assess treatment response. There was a correlation between tumor uptake and cellular targets expression. CONCLUSION: The results indicate that it is feasible to use 99mTc-EC-endostatin to assess efficiency of anti-angiogenesis therapy.

Angiogenesis Inhibitors↗
PubMed2002

Detection of acute postoperative mediastinitis in mice using (99m)Tc-liposomes.

RATIONALE AND OBJECTIVES: To evaluate the usefulness of size-modified (99m)Tc-labeled liposomes for the detection of acute postoperative mediastinitis in a mouse model. METHODS: Fourteen mice underwent low-neck collar incision and had sterile abscesses induced in mediastinum with turpentine. Ten of these animals were injected intravenously with anionic liposomes of 516 +/- 20 nm containing poly(ethylene)glycol labeled with (99m)Tc; the remaining four mice were injected with (67)Ga citrate and used as positive controls. In addition, eight mice either underwent the same surgical procedure but without turpentine (n = 4) or were not operated (n = 4). These were used as negative controls. Therefore, scintigraphy using (99m)Tc-liposomes was performed in eighteen and (67)Ga citrate in four mice. Target area of interest was outlined, and target to background count density ratio and percentage-injected dose were measured. RESULTS: Significant accumulation of radiolabeled liposomes was observed at sites of inflammation within 1 hour in abscess-bearing animals. This correlated well with the findings of the lower quality (contrast) of (67)Ga images at 24 and 48 hours. The radiopharmaceutical did not significantly accumulate in the mediastinum of negative control animals. CONCLUSION: (99m)Tc-liposomes (size modified) may prove useful nonspecific agent for the early diagnosis of postoperative mediastinitis.

Animals↗