Synthesis of Specific SPECT-Radiopharmaceutical for Tumor Imaging Based on Methionine: Tc-99m-DTPA-bis(methionine)
Division Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Brig SK Mazumdar Road, Delhi-110054, India. Bioconjugate Chemistry
(Impact Factor: 4.51).
02/2010; 21(2):229-39. DOI: 10.1021/bc900197n
Methionine-diethylenetriaminepentaaceticacid-methionine [DTPA-bis(Met)] was synthesized by covalently conjugating two molecules of methionine (Met) to DTPA and was labeled with (99m)Tc in high radiochemical purity and specific activity (166-296 MBq/micromol). Kinetic analysis showed K(m) of 12.95 +/- 3.8 nM and a maximal transport rate velocity (V(max)) of 80.35 +/- 0.42 pmol microg protein(-1) min(-1) of (99m)Tc-DTPA-bis(Met) in U-87MG cells. DTPA-bis(Met) had dissociation constants (K(d)) of 0.067 and 0.077 nM in U-87MG and BMG, respectively. (35)S-methionine efflux was trans-stimulated by (99m)Tc-labeled DTPA conjugate demonstrating concentrative transport. The blood kinetic studies showed fast clearance with t(1/2) (F) = 36 +/- 0.5 min and t(1/2) (S) = 5 h 55 min +/- 0.85 min. U-87MG and BMG tumors saturated at approximately 2000 +/- 280 nmol/kg of (99m)Tc-DTPA-bis(Met). Initial rate of transport of (99m)Tc-DTPA-bis(Met) in U-87MG tumor was found to be 4.68 x 10(-4) micromol/kg/min. The tumor (BMG cell line, malignant glioma) grafted in athymic mice were readily identifiable in the gamma images. Semiquantitative analysis from region of interest (ROI) placed over areas counting average counts per pixel with maximum radiotracer uptake on the tumor was found to be 11.05 +/- 3.99 and compared ROI with muscle (0.55 +/- 0.13). The tumor-to-contralateral muscle tissue ratio of (99m)Tc-DTPA-bis(Met) was found to be 23 +/- 3.3. Biodistribution revealed significant tumor uptake and good contrast in the U-87MG, BMG, and EAT tumor-bearing mice. In clinical trials, the sensitivity, specificity, and positive predictive values were found to be 87.8%, 92.8%, and 96.6%, respectively. (99m)Tc-DTPA-bis(Met) showed excellent tumor targeting and has promising utility as a SPECT-radiopharmaceutical for imaging methionine-dependent human tumors and to quantify the ratio of MET(+)/HCY(-).
Available from: Chunhua Yang
- "Tc-DMA complex remain at origin and free technetium rose with the solvent front in acetone (Supplemental Fig. 1) (Hazari et al., 2010; Kumar et al., 2012). "
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ABSTRACT: Radiotherapy, a therapeutic modality of cancer treatment, non-selectively damages normal tissues over tumor tissue as well. A continuous search is going on for the development of therapeutic agents, which selectively reduce radiation induced normal tissue injury without reducing tumoricidal effect, thereby increasing therapeutic ratio of radiation therapy. Our laboratory established 5-(4-methylpiperazin-1-yl)-2-[2'-(3,4-dimethoxyphenyl)-5'benzimidazolyl] benzimi-dazole (DMA) as non-cytotoxic radioprotector in mammalian cells. DMA showed an excellent radioprotection in mice at single nontoxic oral dose by a dose reduction factor (DRF) of 1.28. ORAC assay confirmed its free radical quenching ability. Single bolus dose and 28-days repeated administration of DMA in mice for toxicity studies determined LD50 of >2000 mg/kg bw and 225 mg/kg bw respectively, suggesting DMA is safe. Histopathology, biochemical parameters and relative organ weight analysis revealed insignificant changes in DMA treated animals. Pharmacokinetic study of DMA at oral and intravenous doses showed its Cmax = 1h, bioavailability of 8.84%, elimination half-life of 4h and an enterohepatic recirculation. Biodistribution study in Ehrlich Ascites Tumor (EAT) bearing mice showed that 99mTc-DMA achieved highest concentration in 1h and retained upto 4h in lungs, liver, kidneys and spleen, and in a low concentration in tumor, a solicited property of any radioprotector to protect normal cells over cancerous cells. We observed that single dose treatment of tumor bearing mice with DMA 2h prior to 8 Gy TBI, showed an impressive rescue of radiation induced morbidity, in terms of weight loss and mortality, without a change in tumor response.
The American Society for Pharmacology and Experimental Therapeutics.
Available from: Haiyan Chen
- "Synthesis of Au-near infrared fluorescence probe (His@Au-MPA). MPA was immobilized onto His@Au using coupling agents (EDC and NHS) to increase the reaction yield  "
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ABSTRACT: A facile approach to synthesize gold nanoclusters (Au NCs) with bluish green fluorescence using histidine as both reductant and capping agent was reported. The UV-visible absorption and photoluminescence spectra measurement was performed to explore its optical properties under different circumstances (preparing condition, temperature, pH, storing time). Then, MPA, a NIR organic dye, was conjugated to Au NCs (Au-MPA) for in vivo fluorescence imaging application. Low cytotoxicity and high affinity to tumor of this nanoprobe was proved at the cellular level, and its bio-distribution in normal nude mice and MCF-7 tumor-bearing mice was also investigated. Consequently, the results demonstrated the promising potential of the green Au NCs conjugated with NIR dye as nanoprobes in bioimaging and related fields.
Available from: Bowen Li
- "Retnakumari et al. have successfully synthesized folate modified Au NCs with low cytotoxicity which manifest specifically targeting capability toward oral squamous cell carcinoma (KB) with high level expression of folate receptors in tumor fluorescent imaging . Methionine (Met), which plays a crucial role in reproduction, cell survival, methylation of proteins and DNA, is indispensable for the tumor progression . Increase in the uptake of amino acid, especially methionine, is known to be one of the earliest events associated with in vitro cancerization of cells. "
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ABSTRACT: Gold nanoclusters (NCs) were functionalized as a fluorescent probe and a pro-drug intended for tumor diagnosis and therapy. Firstly, Au NCs were conjugated with methionine (Met) and MPA, a near-infrared (NIR) fluorescent dye, giving a probe, Au-Met-MPA. The tumor targeting capability endowed by Met as well as low cytotoxicity of this contrast agent and its clinical potential for tumor targeting imaging were demonstrated in vitro and in vivo. Secondly, Doxorubicin (DOX), a widely used clinical anti-cancer drug, was immobilized on the methionine modified Au NCs to form a pro-drug, Au-Met-DOX. The enhanced tumor affinity and improved anti-tumor activity of this pro-drug were demonstrated. Results in this study suggest not only the prospect of non-toxic Au NCs modified with functional ligands for tumor-targeted imaging, but also confirm the promising future of Au NCs as a core for the design of pro-drug in the field of cancer therapy.
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