Fazilet Zumrut Biber Muftuler

Synthesis of a Novel Antiestrogen Radioligand (99mTc-TOR-DTPA)

This study was aimed at developing a hydrophilic radioligand as an antiestrogen drug derivative to be used for imaging breast tumors. Toremifene [TOR; 4-chloro-1,2-diphenyl-1-(4-(2-(N,N-di-methylamino)ethoxy)phenyl)-1-butene, as citrate salt] was selected as the starting material to be derived, since it has been used extensively as an antiestrogen drug for treatment and prevention of human breast cancer. An antiestrogen drug derivative, TOR attached to diethylenetriamine pentaacetic acid (DTPA), was synthesized by two experimental treatments, including a purification and a reaction step. We described the synthesis of this TOR derivative, (3Z)-4-{4-[2-(dimethylamino) ethoxy] phenyl}-3,4-diphenylbut-3-en-1-ylN,N-bis[2-(2,6-dioxomorpholin-4-yl)ethyl]glycinate (TOR-DTPA), in detail. Mass spectroscopy confirmed the expected structures. TOR-DTPA was labeled with technetium-99m ((99m)Tc), using stannous chloride (SnCl(2)) as the reducing agent. Biodistribution studies were performed on female Albino Wistar rats. Quality controls, radiochemical yield, and stability studies were done utilizing high-performance liquid chromatography, radioelectrophoresis, thin-layer chromatography, and thin-layer radiochromatography methods. The synthesized compound was found to be hydrophilic and anionic, with high stability for the duration of the testing period in vitro. The results indicated that the radiolabeled compound has estrogen-receptor specificity, especially for the breast tissue. It is highly possible that this compound could be used for imaging breast tumors as a novel technetium-labeled hydrophilic estrogen derivative radioligand.

L-Carnitine Protection Against Cisplatin Nephrotoxicity In Rats: Comparison with Amifostin Using Quantitative Renal Tc 99m DMSA Uptake

Objective: In this study, we aimed to investigate the cytoprotective effect of L-carnitine against cisplatin-induced nephrotoxicity and to compare its efficacy with that of amifostin by quantitative renal Tc 99m DMSA uptake. Material and Methods: Male Wistar rats were randomly divided into six groups of six animals each. 1) Control (saline; 5 ml/kg intraperitoneally); 2) L-carnitine (CAR; 300 mg/kg intraperitoneally); 3) Amifostine (AMI; 200 mg /kg intraperitoneally); 4) Cisplatin (CIS;7 mg/kg intraperitoneally); 5) Cisplatin plus L-carnitine (CIS + CAR); 6) Cisplatin plus amifostine (CIS + AMI). L-carnitine and amifostine were injected 30 minutes before cisplatin in Group 5 and 6. Tc 99m DMSA, 7.4 MBq/0.2 ml, was injected through the tail vein 72 hours after the drug administration. Rats were killed and kidneys removed by dissection 2 hours after the injection of the radiopharmaceutical. The percentage of the injected dose per gram of kidney tissue (%ID/g) was calculated. Renal function was monitored by measuring BUN and plasma levels of creatinine. Lipid peroxidation and glutathione content were determined by measuring malondialdehyde (MDA) and reduced glutathione (GSH) in kidney tissue homogenates. Results: Tc 99m DMSA uptake per gram tissue of the kidney as %ID/g was 29.54±4.72, 29.86 ± 7.47 and 26.37 ± 4.54 in the control, CAR and AMI groups respectively. %ID/g was the lowest of all the groups, 11.60±3.59 (p<0.01), in the cisplatin group. Carnitine or amifostine administration 30 minutes before cisplatin injection resulted a significant increase in %ID/g, 21.28±7.73 and 18.97±3.24 respectively, compared to those of cisplatin-treated rats (p<0.002). A marked increase in plasma BUN and creatinine indicating nephrotoxicity and acute renal failure was observed in the cisplatin-treated group. MDA and GSH levels were concordant with cisplatin-induced oxidative stress in the kidney tissue. Conclusion: The results showed that L-carnitine significantly attenuates the cisplatin-induced nephrotoxicity as amifostin. Conflict of interest:None declared.

Radiolabeling of methanol extracts of yarrow (Achillea millefolium l) in rats

PURPOSE Current study is focused on extraction with methanol, purification, labeling with (131)I using iodogen method of the yarrow plant and investigating in vivo biological activity using biodistribution and imaging studies on healthy animal models. The aim of the study is to contribute plant extracts to discover new drugs in the diagnosis and treatment of several diseases. METHODS Nine female and nine male healthy Wistar albino rats, which were approximately 100-150 g in weight, were used for biodistribution studies. For imaging studies four healthy male Balb-C mice were used. Quality control studies were done utilizing thin layer radio chromatography (TLRC) and high performance liquid chromatography (HPLC) methods. For biodistribution studies, (131)I radiolabeled Peak 7 ((131)I-Peak 7) was sterilized and injected into the tail veil of rats and imaging studies were obtained using Kodak FX PRO in vivo Imaging System. RESULTS The radiolabeling yield of each purified the bioactive extracts of the yarrow plant, seven peaks was between 79 and 92%. The highest radiolabeling yield was calculated for (131)I radiolabeled seventh peak ((131)I-Peak 7) (92.78 ± 5.04, n=5). For this reason the biodistribution and imaging studies were done for (131)I-Peak 7. Thats why; these studies with Peak 7 were carried out. CONCLUSION Peak 7 was radiolabeled with (131)I in high yield for using imaging and therapeutic studies in nuclear medical applications.

Metabolic comparison of radiolabeled aniline- and phenol-phthaleins with 131I

The metabolic comparison of aniline- and phenol-phthaleins radiolabeled with (131)I ((131)I-APH and (131)I-PPH, respectively) has been investigated in this study. To compare the metabolic behavior of these phthaleins and their glucuronide conjugates radiolabeled with (131)I, scintigraphic and biodistributional techniques were applied using male Albino rabbits. The results obtained have shown that these compounds were successfully radioiodinated with a radioiodination yield of about 100%. Maximum uptakes of (131)I-APH and (131)I-PPH, which were metabolized as N- and O-glucuronides, were observed within 2 h in the bladder and in the small intestine, respectively. In the case of verification of considerably up taking of these compounds also by tumors developed in the small intestine and in the bladder tissues, these results can be expected to be encouraging to test these compounds, which will be radiolabeled with other radioiodines such as (125)I, (123)I and (124)I as imaging and therapeutic agents in nuclear medical applications.

Metabolic comparison of radiolabeled bleomycin and bleomycin-glucuronide labeled with 99mTc.

The metabolic comparison of bleomycin (BLM) and bleomycin-glucuronide (BLMG) radiolabeled with (99m)Tc ((99m)Tc-BLM and (99m)Tc-BLMG, respectively) has been investigated in this study. Quality control procedures were carried out using thin-layer radiochromatography and high-performance liquid chromatography. To compare the metabolic behavior of BLM and its glucuronide conjugate radiolabeled with (99m)Tc, scintigraphic, and biodistributional techniques were applied using male New Zealand rabbits and Albino Wistar rats. The results obtained have shown that these compounds were successfully radiolabeled with a labeling yield of about 100%. Maximum uptakes of (99m)Tc-BLM and (99m)Tc-BLMG metabolized as N-glucuronide were observed within 2 hours in the liver, the bladder, and the spinal cord for (99m)Tc-BLM and the lung, the liver, the kidney, the large intestine, and the spinal cord for (99m)Tc-BLMG, respectively. Scintigraphy and biodistributional studies performed on the experimental animals have shown that radiopharmaceutical potentials of these compounds are completely different. At the same time, uptake of the (99m)Tc-BLMG was found to be better than that of (99m)Tc-BLM.

Synthesis of a theranostic agent: radioiodinated PEGylated PLGA-indocyanine capsules and in vitro determination of their bioaffinity on ovarian, cervical and breast cancer cells

The aim of current study is to synthesize a theranostic (multi-functional) agent, which is targeted on ovary, cervical and breast cancer types with diagnosis and treatment potential and to determine its bioaffinity by using in vitro methods. In conclusion; the designed compound (IPPP), which has fluorescence capability (from Indocyanine), encapsulated structure (with PEGylated PLGA), included an anticancer drug (Paclitaxel) for targeting and radionuclidic tracer (131I) content for tracing, has bioaffinity and promise for diagnosis and therapy on ovarian, cervical and breast cancer cell lines.

Investigation of Therapeutic Efficiency of Bleomycin and Bleomycin-Glucuronide Labeled with 131I on the Cancer Cell Lines

The aim of this study is to determine the incorporations of radiolabeled bleomycin ((131)I-BLM) and bleomycin-glucuronide ((131)I-BLMGLU) on PC-3 (human prostate carcinoma cell line), Caco-2 (human colon adenocarcinoma cell line), Hutu-80 (Human Duodenum adenocarcinoma cell line), and A549 (Human lung adenocarcinoma epithelial cell line) cancerous cell lines. For this purpose, BLM and BLMGLU enyzmatically synthesized were labeled with (131)I, quality control studies were done and the incorporation yields of (131)I-BLM and (131)I-BLMGLU on these cell lines were measured. Quality-control studies showed that the radiolabeling yields were obtained as 95% and 90% for (131)I-BLM and (131)I-BLMGLU, respectively. Also, as a result of the cell culture studies, it was found that (131)I-BLM and (131)I-BLMGLU had higher incorporation on PC-3 cells than that of other cell lines. In addition to this, it was reported that the incorporation yield of (131)I-BLMGLU was higher than that (131)I-BLM. At the end of the study, cytotoxicities of BLM and BLMGLU on PC-3 cancerous cell line were inspected and fluorescent images of BLM and BLMGLU were taken on PC-3 cells by using fluorescein isothiocyanate. In conclusion, cell culture studies demonstrated that the incorporation values of (131)I-BLMGLU on the four cell lines were about five to six times higher than (131)I-BLM. Radiolabeled glucuronide derivatives can be used in cancer therapy and tumor imaging, depending on the properties of radioiodine for the β-glucuronidase-rich tissues because glucuronidation leads to rapid and higher incorporation on adenocarcinoma cells.

Bioavailability of 99mTc-paclitaxel-glucuronide (99mTc-PAC-G)

Abstract An antitumor agent paclitaxel (PAC) has been proved to be efficient in the treatment of breast and ovarian cancer. Glucuronic acid-derived paclitaxel compound [paclitaxel-glucuronide (PAC-G)] was enzymatically synthesized using microsome preparate separated from rat livers. The biodistribution mechanism of PAC-G in healthy female Albino Wistar rats has been investigated. The expected structure is confirmed according to LC/MS results, and the possible attachment is to C2-hydroxyl group. PAC-G was labeled with 99mTc and the radiochemical yield of radiolabeled compound (99mTc-PAC-G) was 98.0±02.74 (n=9). The range of the breast/blood and breast/muscle ratios is approximately between 3 and 35 in 240ߙmin. All these experimental studies indicate that 99mTc-PAC-G may potentially be used in breast tissue as an imaging agent.

In Vivo investigation of radiolabeled Bevacizumab in healthy rat tissues

In this study, BevMab was conjugated with the bifunctional chelating agent [diethylenetriamine pentaacetic acid (DTPA)] and the product (BevMab-DTPA) was labeled with 99mTc using stannous chloride reducing method. The quality control studies of radiolabeled compound (99mTc-BevMab-DTPA) were done with Thin Layer Radio Chromatography (TLRC) and High Performance Liquid Radio Chromatography (HPLRC) methods (% 95 <) to confirm the labeling efficiency. High radiochemical yield [98.07 % ± 2.17 (n = 13)] was obtained by TLRC method. Biodistribution studies of 99mTc labeled BevMab-DTPA was run on healthy female and male Albino Wistar rats. The distribution figures demonstrated that the radiolabeled compound was eliminated through the kidneys and accumulated in urinary bladder. The values of the BevMab-DTPA uptakes were similar in heart, blood, liver and spleen in both sexes.

Anti toxic effect of broccoli extract on stannous dichloride toxicity

PURPOSE Since Technetium-99m ((99m)Tc) has favorable physical and chemical characteristics, it is widely used radioisotope in Nuclear Medicine. However, stannous dichloride (SnCl(2)) has been widely used as a reducing agent in labeling procedure of pharmaceutical with radionuclide, it has been realized that SnCl(2) have genotoxic and cytotoxic effects on biological systems. In previous studies, it has been shown that some herbal extract can reduce genotoxic and cytotoxic effects of SnCl(2). In the present study, it is aimed to evaluate the effect of the broccoli extract on the survival of E. coli ATCC 25922 strain against to toxic effects of SnCl(2). METHODS Broccoli was extracted with methanol extraction. HPLC and TLC analysis of broccoli extract were performed. Then antitoxicity and dose response assays were performed on bacterial strain. RESULTS The broccoli extract had dose dependent protective effect against SnCl(2) toxic effect on E. coli. CONCLUSIONS The consumption of broccoli may alter the stannous dichloride toxicity. Broccoli extract may use as a new protective strategies against the toxic effect of SnCl(2) on patients who were taken (99m)Tc radiopharmaceuticals.