Design, preparation, in vitro and in vivo evaluation of Tc-99m-N2S2-Tat(49-57)-bombesin: A target-specific hybrid radiopharmaceutical

作者：Santos Cuevas Clara L; Ferro Flores Guillermina^*; Arteaga de Murphy Consuelo; Ramirez Flor de M; Luna Gutierrez Myrna A; Pedraza Lopez Martha; Garcia Becerra Rocio; Ordaz Rosado David

来源：International Journal of Pharmaceutics, 2009, 375(1-2): 75-83.

DOI：10.1016/j.ijpharm.2009.04.018

• Radiolabeled bombesin
• Hybrid radiopharmaceutical
• Peptide-receptor imaging
• Tat-bombesin

The gastrin-releasing peptide receptor (GRP-r) is over-expressed in various human tumors. Recently, Tc-99m-EDDA/HYNIC-Lys(3)-bombesin (Tc-99m-BN) was reported as a radiopharmaceutical with specific cell GRP-r binding and images in breast cancer patients demonstrated distinct radioactivity accumulation in malignant tissue. The HIV Tat-derived peptide has been used to deliver a large variety of cargoes into cells. Therefore, a new hybrid radiopharmaceutical of type Tc-99m-N2S2-Tat(49-57)-Lys(3)-bombesin (Tc-99m-Tat-BN) would increase cell uptake. The aim of this research was to prepare and assess in vitro and in vivo uptake kinetics in cancer cells of 99mTc-Tat-BN and to compare its cellular internalization with that of Tc-99m-BN. Structures of N2S2-Tat-BN and Tc(O)N2S2-Tat-BN were calculated by an MM procedure. Tc-99m-Tat-BN was synthesized and stability studies carried out by HPLC and ITLC-SG analyses in serum and cysteine solutions. In vitro internalization was tested using human prostate cancer PC-3 cells and breast carcinoma cell lines MDA-MB231 and MCF7. Biodistribution was determined in PC-3 tumor-bearing nude mice. Results showed a minimum energy of 271 kcal/mol for N2S2-Tat-BN and 300 kcallmol for Tc(O)N(2)S(2)Tat-BN. Tc-99m-Tat-BN radiochemical purity was >90%. In vitro studies demonstrated stability in serum and cysteine solutions, specific cell receptor binding and internalization in three cell lines was significantly higher than that of Tc-99m-BN (p<0.05). The tumor-to-muscle radioactivity ratio was 8.5 for Tc-99m-Tat-BN and 7 for Tc-99m-BN. Therefore, this hybrid is potentially useful in breast and prostate cancer imaging.

• 出版日期2009-6-22