Kubra Durkan1, Zongrun Jiang2, Tammy L Rold3, Gary L Sieckman4, Timothy J Hoffman5, Rajendra Prasad Bandari6, Ashley F Szczodroski4, Liqin Liu7, Yubin Miao8, Tamila Stott Reynolds9, Charles J Smith10. 1. Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA; Department of Radiology, University of Missouri School of Medicine, Columbia, MO 65211, USA; Department of Nuclear Applications, Ege University, 35100, Bornova, Izmir, Turkey. Electronic address: kubra.durkan@ege.edu.tr. 2. Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA; Department of Chemistry, University of Missouri, Columbia, MO 65211, USA. 3. Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA; Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO 65211, USA. 4. Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA. 5. Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA; Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO 65211, USA; Department of Chemistry, University of Missouri, Columbia, MO 65211, USA. 6. Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA; Department of Radiology, University of Missouri School of Medicine, Columbia, MO 65211, USA. 7. College of Pharmacy, University of New Mexico, Albuquerque, NM87131, USA. 8. College of Pharmacy, University of New Mexico, Albuquerque, NM87131, USA; Cancer Research and Treatment Center, University of New Mexico, , Albuquerque, NM 8713, 1USA; Department of Dermatology, University of New Mexico, Albuquerque, NM 87131, USA. 9. Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA; Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO 65211, USA. 10. Research Division, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA; Department of Radiology, University of Missouri School of Medicine, Columbia, MO 65211, USA; University of Missouri Research Reactor Center, University of Missouri, Columbia, MO 65211, USA. Electronic address: smithcj@health.missouri.edu.
Abstract
INTRODUCTION: In the present study, we describe a (64)Cu-radiolabeled heterodimeric peptide conjugate for dual αvβ3/GRPr (αvβ3 integrin/gastrin releasing peptide receptor) targeting of the form [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2] (RGD: the amino acid sequence [Arg-Gly-Asp], a nonregulatory peptide used for αvβ3 integrin receptor targeting; Glu: glutamic acid; NO2A: 1,4,7-triazacyclononane-1,4-diacetic acid; 6-Ahx: 6-amino hexanoic acid; and RM2: (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2), an antagonist analogue of bombesin (BBN) peptide used for GRPr targeting). METHODS: RGD-Glu-6Ahx-RM2] was conjugated to a NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) complexing agent to produce [RGD-Glu-[NO2A]-6-Ahx-RM2], which was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) and characterized by electrospray ionization-mass spectrometry (ESI-MS). Radiolabeling of the conjugate with (64)Cu produced [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2 in high radiochemical yield (≥95%). In vivo behavior of the radiolabeled peptide conjugate was investigated in normal CF-1 mice and in the PC-3 human prostate cancer experimental model. RESULTS: A competitive displacement receptor binding assay in human prostate PC-3 cells using (125)I-[Tyr(4)]BBN as the radioligand showed high binding affinity of [RGD-Glu-[(nat)Cu-NO2A]-6-Ahx-RM2] conjugate for the GRPr (3.09±0.34 nM). A similar assay in human, glioblastoma U87-MG cells using (125)I-Echistatin as the radioligand indicated a moderate receptor-binding affinity for the αvβ3 integrin (518±37.5 nM). In vivo studies of [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2] showed high accumulation (4.86±1.01 %ID/g, 1h post-intravenous injection (p.i.)) and prolonged retention (4.26±1.23 %ID/g, 24h p.i.) of tracer in PC-3 tumor-bearing mice. Micro-positron emission tomography (microPET) molecular imaging studies produced high-quality, high contrast images in PC-3 tumor-bearing mice at 4h p.i. CONCLUSIONS: The favorable pharmacokinetics and enhanced tumor uptake of (64)Cu-NOTA-RGD-Glu-6Ahx-RM2 warrant further investigations for dual integrin and GRPr-positive tumor imaging and possible radiotherapy.
INTRODUCTION: In the present study, we describe a (64)Cu-radiolabeled heterodimeric peptide conjugate for dual αvβ3/GRPr (αvβ3 integrin/gastrin releasing peptide receptor) targeting of the form [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2] (RGD: the amino acid sequence [Arg-Gly-Asp], a nonregulatory peptide used for αvβ3 integrin receptor targeting; Glu: glutamic acid; NO2A: 1,4,7-triazacyclononane-1,4-diacetic acid; 6-Ahx: 6-amino hexanoic acid; and RM2: (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2), an antagonist analogue of bombesin (BBN) peptide used for GRPr targeting). METHODS:RGD-Glu-6Ahx-RM2] was conjugated to a NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) complexing agent to produce [RGD-Glu-[NO2A]-6-Ahx-RM2], which was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) and characterized by electrospray ionization-mass spectrometry (ESI-MS). Radiolabeling of the conjugate with (64)Cu produced [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2 in high radiochemical yield (≥95%). In vivo behavior of the radiolabeled peptide conjugate was investigated in normal CF-1 mice and in the PC-3humanprostate cancer experimental model. RESULTS: A competitive displacement receptor binding assay in human prostate PC-3 cells using (125)I-[Tyr(4)]BBN as the radioligand showed high binding affinity of [RGD-Glu-[(nat)Cu-NO2A]-6-Ahx-RM2] conjugate for the GRPr (3.09±0.34 nM). A similar assay in human, glioblastomaU87-MG cells using (125)I-Echistatin as the radioligand indicated a moderate receptor-binding affinity for the αvβ3 integrin (518±37.5 nM). In vivo studies of [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2] showed high accumulation (4.86±1.01 %ID/g, 1h post-intravenous injection (p.i.)) and prolonged retention (4.26±1.23 %ID/g, 24h p.i.) of tracer in PC-3tumor-bearing mice. Micro-positron emission tomography (microPET) molecular imaging studies produced high-quality, high contrast images in PC-3tumor-bearing mice at 4h p.i. CONCLUSIONS: The favorable pharmacokinetics and enhanced tumor uptake of (64)Cu-NOTA-RGD-Glu-6Ahx-RM2 warrant further investigations for dual integrin and GRPr-positive tumor imaging and possible radiotherapy.
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