Radiolabeling of NOTA and DOTA with Positron Emitting 68Ga and

Purpose: We established radiolabeling conditions of NOTA and DOTA with a generator-produced PET radionuclide 68Ga and studied in vitro characteristics such as stability, serum protein binding, octanol/water distribution, and interference with other metal ions. Materials and Methods: Various concentrations of NOTA․3HCl and DOTA․ 4HCl were labeled with 1 mL 68GaCl3 (0.18～5.75 mCi in 0.1 M HCl) in various pH. NOTA․3HCl (0.373 mM) was labeled with 68GaCl3 (0.183～0.232 mCi/0.1 M HCl 1.0 mL) in the presense of CuCl2, FeCl2, InCl3, FeCl3, GaCl3, MgCl2 or CaCl2 (0～6.07 mM) at room temperature. The labeling efficiencies of 68Ga-NOTA and 68Ga-DOTA were checked by ITLC-SG using acetone or saline as mobile phase. Stabilities, protein bindings, and octanol distribution coefficients of the labeled compounds also were investigated. Results: 68Ga-NOTA and 68Ga-DOTA were labeled optimally at pH 6.5 and pH 3.5, respectively, and the chelates were stable for 4 hr either in the reaction mixture at room temperature or in the human serum at 37°C. NOTA was labeled at room temperature while DOTA required heating for labeling. 68Ga-NOTA labeling efficiency was reduced by CuCl2, FeCl2, InCl2, FeCl3 or GaCl3, however, was not influenced by MgCl2 or CaCl2. The protein binding was low (2.04~3.32%). Log P value of 68Ga-NOTA was -3.07 indicating high hydrophilicity. Conclusion: We found that NOTA is a better bifunctional chelating agent than DOTA for 68Ga labeling. Although, 68Ga-NOTA labeling is interfered by various metal ions, it shows high stability and low serum protein binding.한국과학재단 국가지정연구실사업 (R0A-2008-000- 20116-0) 및 원자력연구개발사업 (2007-01238

Thyroid-Related Protein Expression in the Human Thymus

Radioiodine whole body scan (WBS), related to sodium iodide symporter (NIS) function, is widely used to detect recurrence/metastasis in postoperative patients with thyroid cancer. However, the normal thymic uptake of radioiodine has occasionally been observed in young patients. We evaluated the expression of thyroid-related genes and proteins in the human thymus. Thymic tissues were obtained from 22 patients with thyroid cancer patients of all ages. The expression of NIS, thyroid-stimulating hormone receptor (TSHR), thyroperoxidase (TPO), and thyroglobulin (Tg) was investigated using immunohistochemistry and quantitative RT-PCR. NIS and TSHR were expressed in 18 (81.8%) and 19 samples (86.4%), respectively, whereas TPO was expressed in five samples (22.7%). Three thyroid-related proteins were localized to Hassall’s corpuscles and thymocytes. In contrast, Tg was detected in a single patient (4.5%) localized to vascular endothelial cells. The expression of thyroid-related proteins was not increased in young thymic tissues compared to that in old thymic tissues. In conclusion, the expression of NIS and TSHR was detected in the majority of normal thymus samples, whereas that of TPO was detected less frequently, and that of Tg was detected rarely. The increased thymic uptake of radioiodine in young patients is not due to the increased expression of NIS

Radioiodine Therapy in Differentiated Thyroid Cancer: The First Targeted Therapy in Oncology

Iodide uptake across the membranes of thyroid follicular cells and cancer cells occurs through an active transport process mediated by the sodium-iodide symporter (NIS). The rat and human NIS-coding genes were cloned and identified in 1996. Evaluation of NIS gene and protein expression is critical for the management of thyroid cancer, and several approaches to increase NIS levels have been tried. Identification of the NIS gene has provided a means of expanding its role in radionuclide therapy and molecular target-specific theragnosis (therapy and diagnosis using the same molecular target). In this article, we describe the relationship between NIS expression and the thyroid carcinoma treatment using I-131 and alternative therapeutic approaches

A new PET probe, (18)F-tetrafluoroborate, for the sodium/iodide symporter: possible impacts on nuclear medicine

As early as 1915, it was found that iodide is required in the thyroid gland for the production of thyroid hormones. Since then, radioiodines have been used as tracers in thyroid function tests and as agents for the treatment of hyperthyroidism and benign thyroid diseases. Furthermore, knowledge of the importance of the role played by iodine transport in thyroid cancer cells provides the rationale for the use of radioiodines to diagnose and treat thyroid cancer (1, 2). In fact, the clinical utilization of radioiodines led to the birth of nuclear medicine. Today, it is known that the iodide pump is a sodium/iodide symporter (NIS), an intrinsic membrane protein of the thyroid gland follicular cells (3, 4), and that the NIS-catalysed accumulation of iodide in cells from the interstitium is achieved against its transmembrane electrochemical gradient, which is maintained by sodium-potassium adenosine triphosphatase. The identification of the human NIS (hNIS) gene created many new diagnostic and therapeutic opportunities, and in particular, researchers are currently investigating the use of hNIS as a reporter gene for gene therapy and molecular and genomic imaging (5).Jauregui-Osoro M, 2010, EUR J NUCL MED MOL I, V37, P2108, DOI 10.1007/s00259-010-1523-0CHUNG JK, 2010, NUCL MED MOL IMAGING, V44, P4Freudenberg LS, 2007, NUKLEARMED-NUCL MED, V46, P121, DOI 10.1160/nukmed-0076FERNANDES JK, 2005, CURR TREAT OPTION ON, V6, P47Sgouros G, 2004, J NUCL MED, V45, P1366Chung JK, 2004, EUR J NUCL MED MOL I, V31, P799, DOI 10.1007/s00259-004-1475-3Van Sande J, 2003, ENDOCRINOLOGY, V144, P247, DOI 10.1210/en.2002-220744Chung JK, 2002, J NUCL MED, V43, P1188Eschmann SM, 2002, EUR J NUCL MED MOL I, V29, P760, DOI 10.1007/s00259-002-0775-8Min JJ, 2001, EUR J NUCL MED, V28, P639Filetti S, 1999, EUR J ENDOCRINOL, V141, P443Caillou B, 1998, J CLIN ENDOCR METAB, V83, P4102Dai G, 1996, NATURE, V379, P458LAMBRECHT RM, 1988, J RADIOAN NUCL CH LE, V127, P143ANBAR M, 1960, ENDOCRINOLOGY, V66, P888ANBAR M, 1959, NATURE, V183, P1517

인대뇌(人大腦) 중심전회(中心前回)와 도중심전회(島中心前回) 각피질봉부간(各皮質峯部間)의 비교세포구축학(比較細胞構築學) 및 양피질(兩皮質)의 가령영향(加齡影響)에 관한 연구

The cytoarchitectures of the Brodmann's cortical area 4 and 52 were compared along with the effects of aging and weight increase on both areas. Samples were taken from 209 brains for area 4 and 153 brains for area 52. Cortical thickness, relative total neuronal density (RTND), and relative total glial cell density (RTGD) were studied and statistically significant differences between each age-or brain weight-group were examined. The following results were obtained: 1. No difference between the cortical thickness of the two cortical areas was noticed in regard to age, side and sex. 2. There was no significant difference between RTND of most of the age-or brain weightgroups of the two areas of the same side brains. 3. Difference was shown between RTGD of 0-1 age group of area 4 and that of some age groups of area 52 of the same side brains and also between those of some brain weightgroups of the two cortical areas. 4. Mostly, sex or side didn't seem to cause different result in the above comparisons

Differential receptor targeting of liver cells using 99mTc-neoglycosylated human serum albumins

Neolactosyl human serum albumin (LSA) targets asialoglycoprotein receptor and shows high liver uptake due to accumulation in hepatocytes. Although neomannosyl human serum albumin (MSA) also shows high liver uptake, it has been reported to be taken up by Kupffer cells and endothelial cells. We compared the biological properties of LSA and MSA. 99mTc-LSA and 99mTc-MSA biodistribution in mice were investigated after intravenous injection. In vivo localization of rhodaminisothiocyanate (RITC)-LSA and fluoresceineisothiocyanate (FITC)-MSA were investigated in mouse liver. Excretion routes of 99mTc-LSA and 99mTc-MSA metabolites were examined. Both 99mTc-LSA and 99mTc-MSA showed high liver uptakes. RITC-LSA was taken up by hepatocytes whereas FITC-MSA was taken up by Kupffer cells and endothelial cells. 99mTc-MSA showed higher spleen and kidney uptakes than 99mTc-LSA. 99mTc-LSA metabolites excreted in urine and feces accounted for 44.4 and 50.0% of 99mTc-LSA injected, respectively, while 99mTc-MSA metabolites accounted for 51.5 and 10.3%, respectively. In conclusion, LSA is specifically taken up by hepatcytes while MSA by Kupffer cells and endothelial cells. After taken up by the liver, LSA is metabolized by the hepatocytes and then excreted through both the hepatobiliary tract and kidney, whereas MSA is metabolized by Kupffer cells and endoghelial cells and then excreted mainly through the kidney

Comprehensive gene expression analysis for exploring the association between glucose metabolism and differentiation of thyroid cancer

Background The principle of loss of iodine uptake and increased glucose metabolism according to dedifferentiation of thyroid cancer is clinically assessed by imaging. Though these biological properties are widely applied to appropriate iodine therapy, the understanding of the genomic background of this principle is still lacking. We investigated the association between glucose metabolism and differentiation in advanced thyroid cancer as well as papillary thyroid cancer (PTC). Methods We used RNA sequencing of 505 patients with PTC obtained from the Cancer Genome Archives and microarray data of poorly-differentiated and anaplastic thyroid cancer (PDTC/ATC). The signatures of GLUT and glycolysis were estimated to assess glucose metabolic profiles. The glucose metabolic profiles were associated with tumor differentiation score (TDS) and BRAFV600E mutation status. In addition, survival analysis of glucose metabolic profiles was performed for predicting recurrence-free survival. Results In PTC, the glycolysis signature was positively correlated with TDS, while the GLUT signature was inversely correlated with TDS. These correlations were significantly stronger in the BRAFV600E negative group than the positive group. Meanwhile, both GLUT and glycolysis signatures were negatively correlated with TDS in advanced thyroid cancer. The high glycolysis signature was significantly associated with poor prognosis in PTC in spite of high TDS. The glucose metabolic profiles are intricately associated with tumor differentiation in PTC and PDTC/ATC. Conclusions As glycolysis was an independent prognostic marker, we suggest that the glucose metabolism features of thyroid cancer could be another biological progression marker different from differentiation and provide clinical implications for risk stratification. Trial registration Not applicable.This research was supported by grant no. 2620180060 from the SNUH Research Fund and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI19C0339). The funder had no role in designing the study, in collection, analysis, and interpretation of data, or in writing the manuscript

Wild-type p53 enhances the cytotoxic effect of radionuclide gene therapy using sodium iodide symporter in a murine anaplastic thyroid cancer model

To evaluate the role of p53 in radionuclide gene therapy, we investigated the cytotoxic effect of (131)I and (188)Re following cotransfection of the sodium iodide symporter (NIS) and wild-type p53 (wt-p53) genes into cancer cells. The NIS gene was transfected to human anaplastic thyroid carcinoma cells (ARO) expressing mutant p53 (mt-p53) using liposomes. The uptakes of (125)I and (188)Re were measured in the transfected (ARO-N) and wild-type cell lines (ARO). A recombinant adenovirus-5 vector containing a CMV promoter and wt-p53 cDNA, called Ad-p53, was established and transduced to ARO and ARO-N cells. After incubating cells with (131)I and (188)Re, the survival rate of each cell line was measured using a clonogenic assay. For radionuclide gene therapy in an animal model, Ad-p53 was injected directly into ARO and ARO-N tumours which were transplanted to nude mice. Two days later, (188)Re or saline was injected intraperitoneally into the mice, and the tumours were measured using a calliper for 4 weeks. In ARO-N cells, the uptakes of (125)I and (188)Re were 505.16 +/- 21.30 pmol/10(6) cells and 13,875.20 +/- 504.85 cpm/10(6) cells at 30 min, respectively. There was no difference between the survival rates of ARO cells and ARO-N cells after incubation with (131)I or (188)Re. When Ad-p53 was transduced to ARO-N cells, the survival rate of wt-p53-expressing ARO-N cells incubated with (131)I (18.5 MBq/5 ml) and (188)Re (18.5 MBq/5 ml) decreased to 48.8 +/- 18.4% and 32.6 +/- 23.5%, respectively. In the nude mice experiment, ARO and ARO-N tumours gradually grew up to six to eight times larger than the initial volume. ARO and ARO-N tumours transduced with Ad-p53 continued to grow. However, the ARO-N tumours treated with Ad-p53 and 185 MBq of (188)Re regressed to 20% of the initial volume. Growth of ARO-N tumour treated with (131)I or (188)Re was significantly inhibited by Ad-p53 transduction in vivo as well as in vitro. Transfection of the NIS gene into human anaplastic thyroid cancer induced the accumulation of beta-emitter radionuclides, and cotransfection with a wt-p53 gene enhanced the cytotoxic effect.This work was supported by a Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2003-E-00168)Hsieh YJ, 2007, ANTICANCER RES, V27, P2515D`Avenia P, 2006, CANCER LETT, V231, P102, DOI 10.1016/j.canlet.2005.01.033Lopez-Crapez E, 2005, BRIT J CANCER, V92, P2114, DOI 10.1038/sj.bjc.6602622Lee YJ, 2004, THYROID, V14, P889Freytag SO, 2004, EXPERT OPIN BIOL TH, V4, P1757, DOI 10.1015/14712598.4.11.1757Lee WW, 2003, ONCOL REP, V10, P845Dohan O, 2003, ENDOCR REV, V24, P48, DOI 10.1210/er.2001-0029Heltemes LM, 2003, CANCER GENE THER, V10, P14Carlin S, 2002, NUCL MED BIOL, V29, P729Chung JK, 2002, J NUCL MED, V43, P1188Dadachova E, 2002, NUCL MED BIOL, V29, P13Sasaki R, 2001, INT J RADIAT ONCOL, V51, P1336Huang M, 2001, CANCER GENE THER, V8, P612Haberkorn U, 2001, J NUCL MED, V42, P317Kawabe S, 2001, INT J RADIAT BIOL, V77, P185Colletier PJ, 2000, INT J RADIAT ONCOL, V48, P1507Nakamoto Y, 2000, J NUCL MED, V41, P1898Arturi F, 2000, EUR J ENDOCRINOL, V143, P623Smit JWA, 2000, THYROID, V10, P939Nagayama Y, 2000, J CLIN ENDOCR METAB, V85, P4081Boland A, 2000, CANCER RES, V60, P3484Horowitz J, 1999, CURR OPIN MOL THER, V1, P500Mandell RB, 1999, CANCER RES, V59, P661Shimura H, 1997, ENDOCRINOLOGY, V138, P4493Siles E, 1996, BRIT J CANCER, V73, P581LAMIOKI H, 1994, RADIOCHIM ACTA, V65, P39MAHESHWARI YK, 1981, CANCER, V47, P664