title: Radiochemical investigations of 177Lu-DOTA-8-Aoc-BBN[7-14]NH2: an in vitro/in vivo assessment of the targeting ability of this new radiopharmaceutical for PC-3 human prostate cancer cells.
abstract: Bombesin (BBN), a 14 amino acid peptide, is an analogue of human gastrin releasing peptide (GRP) that binds to GRP receptors (GRPr) with high affinity and specificity. The GRPr is over expressed on a variety of human cancer cells including prostate, breast, lung, and pancreatic cancers. The specific aim of this study was to identify a BBN analogue that can be radiolabeled with (177)Lu and maintains high specificity for GRPr positive prostate cancer tumors in vivo. A preselected synthetic sequence via solid phase peptide synthesis (SPPS) was designed to produce a DOTA-BBN (DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid) conjugate with the following general structure: DOTA-X-Q-W-A-V-G-H-L-M-(NH(2)), where the spacer group, X = omega-NH(2)(CH(2))(7)COOH (8-Aoc). The BBN-construct was purified by reversed phase-HPLC (RP-HPLC). Electrospray Mass Spectrometry (ES-MS) was used to characterize both metallated and non-metallated BBN-conjugates. The new DOTA-conjugate was metallated with (177)Lu(III)Cl(3) or non-radioactive Lu(III)Cl(3). The (177)Lu(III)- and non-radiolabeled Lu(III)-conjugates exhibit the same retention times under identical RP-HPLC conditions. The (177)Lu-DOTA-8-Aoc-BBN[7-14]NH(2) conjugate was found to exhibit optimal pharmacokinetic properties in CF-1 normal mice. In vitro and in vivo models demonstrated the ability of the (177)Lu-DOTA-8-Aoc-BBN[7-14]NH(2) conjugate to specifically target GRP receptors expressed on PC-3 human prostate cancer cells.
authors.affiliation: Department of Radiology, University of Missouri-Columbia School of Medicine, Columbia, MO 65211, USA.
authors.forename: C Jeffrey
authors.initials: CJ
authors.lastname: Smith
authors.forename: Hariprasad
authors.initials: H
authors.lastname: Gali
authors.forename: Gary L
authors.initials: GL
authors.lastname: Sieckman
authors.forename: Donald L
authors.initials: DL
authors.lastname: Hayes
authors.forename: Nellie K
authors.initials: NK
authors.lastname: Owen
authors.forename: Dana G
authors.initials: DG
authors.lastname: Mazuru
authors.forename: Wynn A
authors.initials: WA
authors.lastname: Volkert
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001839:Bombesin / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D010446:Peptide Fragments / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011471:Prostatic Neoplasms / Q000097:blood / Q000000981:diagnostic imaging* / Q000378:metabolism*; D011874:Radiometry / Q000379:methods; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics; D018004:Receptors, Bombesin / Q000378:metabolism*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: C478093:177Lu-DOTA-8-aminooctanoylbombesin (7-14)-amide; D014408:Biomarkers, Tumor; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D001839:Bombesin