Synthesis of specific SPECT-radiopharmaceutical for tumor imaging based on methionine: 99mTc-DTPA-bis(methionine).
ABSTRACT 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(-).
Article: Multifunctional near-infrared-emitting nano-conjugates based on gold clusters for tumor imaging and therapy.[show abstract] [hide abstract]
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.Biomaterials 08/2012; 33(33):8461-76. · 7.40 Impact Factor