TY - JOUR
T1 - Matched-pair, 86Y/90Y-labeled, bivalent RGD/bombesin antagonist, [RGD-Glu-[DO3A]-6-Ahx-RM2], as a potential theranostic agent for prostate cancer
AU - Bandara, Nilantha
AU - Stott Reynolds, Tamila J.
AU - Schehr, Rebecca
AU - Bandari, Rajendra P.
AU - Diebolder, Philipp J.
AU - Krieger, Stephanie
AU - Xu, Jingli
AU - Miao, Yubin
AU - Rogers, Buck E.
AU - Smith, Charles J.
N1 - Publisher Copyright:
© 2018
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Introduction: In this study, we describe development of a true matched-pair theranostic agent that is able to target the αVβ3 integrin and the gastrin releasing peptide receptor (GRPR). We herein describe methods to metallate and characterize the new conjugate and to validate its biological efficacy by in vitro and in vivo methods. Methods: We have previously described the development of [RGD-Glu-6Ahx-RM2] (where RGD: Arg-Gly-Asp; Glu: glutamic acid; 6-Ahx: 6-amino hexanoic acid; RM2: (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2)) that has been conjugated to a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) bifunctional chelating agent (BFCA) to afford [RGD-Glu-[DO3A]-6-Ahx-RM2] peptide. In this study, we have radiolabeled [RGD-Glu-[DO3A]-6-Ahx-RM2] peptide with 86Y or 90Y. Natural-metallated (natY) conjugates were assessed for binding affinity for the αVβ3 integrin or GRPR in human glioblastoma U87-MG and prostate PC-3 cell lines, respectively. The effective stability of the new tracers was also evaluated prior to in vivo evaluation in normal CF-1 mice and SCID mice bearing xenografted tumors. Results: Competitive displacement binding assays in PC-3 cells showed high binding affinity for the GRPR (IC50, 5.65 ± 0.00 nM). On the other hand, competitive displacement binding assays in U87-MG cells revealed only moderate binding to the αVβ3 integrin (IC50, 346 ± 5.30 nM). Biodistribution studies in PC-3 tumor-bearing mice [RGD-Glu-[[90Y]Y-DO3A]-6-Ahx-RM2] showed high tumor uptake (8.70 ± 0.35%ID/g at 1 h post-intravenous injection) and retention of tracer (5.28 ± 0.12%ID/g) at 24 h post-intravenous injection. Micro-positron emission tomography (microPET) in PC-3 tumor-bearing mice using [RGD-Glu-[[86Y]Y-DO3A]-6-Ahx-RM2] correlated well with biodistribution investigations over the various time points that were studied. Conclusions: The [RGD-Glu-[[86Y]Y-DO3A]-6-Ahx-RM2] and [RGD-Glu-[[90Y]Y-DO3A]-6-Ahx-RM2] matched-pair conjugates described herein exhibit favorable microPET and pharmacokinetic profiles and merit further investigations for molecular imaging and/or therapeutic evaluation in larger animal models and potentially humans. Advances in knowledge and implications for patient care: The theranostic, heterobivalent, agents described herein perform comparably with other mono- and multivalent conjugates we have reported and offer the potential of improved sensitivity for detecting prostate cancer cells that might exhibit differing profiles of receptor expression on tumor cells in human patients.
AB - Introduction: In this study, we describe development of a true matched-pair theranostic agent that is able to target the αVβ3 integrin and the gastrin releasing peptide receptor (GRPR). We herein describe methods to metallate and characterize the new conjugate and to validate its biological efficacy by in vitro and in vivo methods. Methods: We have previously described the development of [RGD-Glu-6Ahx-RM2] (where RGD: Arg-Gly-Asp; Glu: glutamic acid; 6-Ahx: 6-amino hexanoic acid; RM2: (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2)) that has been conjugated to a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) bifunctional chelating agent (BFCA) to afford [RGD-Glu-[DO3A]-6-Ahx-RM2] peptide. In this study, we have radiolabeled [RGD-Glu-[DO3A]-6-Ahx-RM2] peptide with 86Y or 90Y. Natural-metallated (natY) conjugates were assessed for binding affinity for the αVβ3 integrin or GRPR in human glioblastoma U87-MG and prostate PC-3 cell lines, respectively. The effective stability of the new tracers was also evaluated prior to in vivo evaluation in normal CF-1 mice and SCID mice bearing xenografted tumors. Results: Competitive displacement binding assays in PC-3 cells showed high binding affinity for the GRPR (IC50, 5.65 ± 0.00 nM). On the other hand, competitive displacement binding assays in U87-MG cells revealed only moderate binding to the αVβ3 integrin (IC50, 346 ± 5.30 nM). Biodistribution studies in PC-3 tumor-bearing mice [RGD-Glu-[[90Y]Y-DO3A]-6-Ahx-RM2] showed high tumor uptake (8.70 ± 0.35%ID/g at 1 h post-intravenous injection) and retention of tracer (5.28 ± 0.12%ID/g) at 24 h post-intravenous injection. Micro-positron emission tomography (microPET) in PC-3 tumor-bearing mice using [RGD-Glu-[[86Y]Y-DO3A]-6-Ahx-RM2] correlated well with biodistribution investigations over the various time points that were studied. Conclusions: The [RGD-Glu-[[86Y]Y-DO3A]-6-Ahx-RM2] and [RGD-Glu-[[90Y]Y-DO3A]-6-Ahx-RM2] matched-pair conjugates described herein exhibit favorable microPET and pharmacokinetic profiles and merit further investigations for molecular imaging and/or therapeutic evaluation in larger animal models and potentially humans. Advances in knowledge and implications for patient care: The theranostic, heterobivalent, agents described herein perform comparably with other mono- and multivalent conjugates we have reported and offer the potential of improved sensitivity for detecting prostate cancer cells that might exhibit differing profiles of receptor expression on tumor cells in human patients.
KW - Bombesin
KW - Prostate cancer
KW - RGD
KW - RM2
KW - Yttrium
UR - http://www.scopus.com/inward/record.url?scp=85048710758&partnerID=8YFLogxK
U2 - 10.1016/j.nucmedbio.2018.06.001
DO - 10.1016/j.nucmedbio.2018.06.001
M3 - Article
C2 - 29929115
AN - SCOPUS:85048710758
SN - 0969-8051
VL - 62-63
SP - 71
EP - 77
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
ER -