title: Heterobivalent dual-target probe for targeting GRP and Y1 receptors on tumor cells.
abstract: Receptor targeting ligands for imaging and/or therapy of cancer are limited by heterogeneity of receptor expression by tumor cells, both inter-patient and intra-patient. It is often more important for imaging agents to identify local and distant spread of disease than it is to identify a specific receptor presence. Two natural hormone peptide receptors, GRPR and Y1, are specifically interesting because expression of GRPR, Y1 or both is up-regulated in most breast cancers. We describe here the design and development of a new heterobivalent peptide ligand, truncated bombesin (t-BBN)/BVD15-DO3A, for dual-targeting of GRPR and Y1, and validation of its dual binding capability. Such a probe should be useful in imaging cells, tissues and tumors that are GRPR and/or Y1 positive and should target radioisotopes, for example, (68)Ga and/or (177)Lu, to more tumors cells than single GRPR or Y1 targeted probes. A GRP targeting ligand, J-G-Abz4-QWAVGHLM-NH(2) (J-G-Abz4-t-BBN), and an Y1 targeting ligand, INP-K[ε-J-(α-DO3A-ε-DGa)-K]-YRLRY-NH(2)([ε-J-(α-DO3A-ε-DGa)-K]-BVD-15), were synthesized and coupled to produce the heterobivalent ligand, t-BBN/BVD15-DO3A. Competitive displacement binding assays using t-BBN/BVD15-DO3A against (125)I-Tyr(4)-BBN yielded an IC(50) value of 18 ± 0.7 nM for GRPR in T-47D cells, a human breast cancer cell line. A similar assay using t-BBN/BVD15-DO3A against porcine (125)I-NPY showed IC(50) values of 80 ± 11 nM for Y1 receptor in MCF7 cells, another human breast cancer cell line. In conclusion, it is possible to construct a single DO3A chelate containing probe that can target both GRPR and Y1 on human tumor cells.
authors.affiliation: Department of Radiology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Shrivastava
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Wang
authors.forename: Natarajan
authors.initials: N
authors.lastname: Raju
authors.forename: Izabela
authors.initials: I
authors.lastname: Gierach
authors.forename: Haiming
authors.initials: H
authors.lastname: Ding
authors.forename: Michael F
authors.initials: MF
authors.lastname: Tweedle
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D018004:Receptors, Bombesin / Q000235:genetics / Q000378:metabolism*; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D013552:Swine
chemical_list: D008024:Ligands; D010455:Peptides; D018004:Receptors, Bombesin; D017476:Receptors, Neuropeptide Y