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Radiolabeled bivalent peptide ligand...

Jiang, Zongrun.

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Radiolabeled bivalent peptide ligands for prostate cancer imaging.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Radiolabeled bivalent peptide ligands for prostate cancer imaging./
作者:	Jiang, Zongrun.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2015,
面頁冊數:	118 p.
附註:	Source: Dissertation Abstracts International, Volume: 78-03(E), Section: B.
Contained By:	Dissertation Abstracts International78-03B(E).
標題:	Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10180818
ISBN:	9781369294842

Radiolabeled bivalent peptide ligands for prostate cancer imaging.
Jiang, Zongrun.

Radiolabeled bivalent peptide ligands for prostate cancer imaging. - Ann Arbor : ProQuest Dissertations & Theses, 2015 - 118 p.

Source: Dissertation Abstracts International, Volume: 78-03(E), Section: B.

Thesis (Ph.D.)--University of Missouri - Columbia, 2015.

Peptide ligand has been a field of great interest for decades due to its capability of binding to specific receptors that are over-expressed in human tumors. Currently, the so-called bivalent peptide ligand, a radiotracer that has two types of targeting motifs for two different biomarkers, has become an active field of research. The synthesis, characterizations, and in vitro/in vivo biological evaluations of bivalent peptide ligands are discussed in this dissertation. The goal of the thesis was to produce, characterize, radiolabeled with suitable radionuclides ( 67/68Ga/64Cu), and in vitro/ in vivo evaluate bivalent ligands that contain two of the targeting motifs.

ISBN: 9781369294842Subjects--Topical Terms:

518028
Biochemistry.

Radiolabeled bivalent peptide ligands for prostate cancer imaging.
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100 1 $a Jiang, Zongrun. $3 3284486
245 1 0 $a Radiolabeled bivalent peptide ligands for prostate cancer imaging.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2015
300 $a 118 p.
500 $a Source: Dissertation Abstracts International, Volume: 78-03(E), Section: B.
500 $a Adviser: Silvia S. Jurisson.
502 $a Thesis (Ph.D.)--University of Missouri - Columbia, 2015.
520 $a Peptide ligand has been a field of great interest for decades due to its capability of binding to specific receptors that are over-expressed in human tumors. Currently, the so-called bivalent peptide ligand, a radiotracer that has two types of targeting motifs for two different biomarkers, has become an active field of research. The synthesis, characterizations, and in vitro/in vivo biological evaluations of bivalent peptide ligands are discussed in this dissertation. The goal of the thesis was to produce, characterize, radiolabeled with suitable radionuclides ( 67/68Ga/64Cu), and in vitro/ in vivo evaluate bivalent ligands that contain two of the targeting motifs.
520 $a My first aim was to synthesize and investigate a GRPR/PSMA dual targeting bivalent ligand. The bivalent ligand conjugate, [DUPA-6-Ahx-(NODAGA)-5-Ava- BBN(7-14)NH2], was synthesized, purified by reversed-phase high performance liquid chromatography (RP-HPLC), confirmed via electrospray ionization mass spectrometry (ESI-MS), and then metallated with nat/64CuCl 2. The metallated ligand, [DUPA-6-Ahx-(natCu-NODAGA)-5-Ava-BBN(7-14)NH 2], was evaluated in vitro via competitive displacement binding assays (IC50 = 11.1 +/- 0.46 nM in PC-3 cells, IC 50 = 1.16 +/- 1.35 nM in LNCaP cells). MicroPET/CT images of PC-3 tumor-bearing severe combined immunodeficient (SCID) and LNCaP tumor-bearing athymic nude mice were obtained at 18 h post-injection (p.i.) of [DUPA-6-Ahx-( natCu-NODAGA)-5-Ava-BBN(7-14)NH2]. The study demonstrated the capability of the bivalent ligand to target both biomarkers. However, further optimizations of the ligand are warranted for superior pharmacokinetics in vivo..
520 $a My second aim was to synthesize and investigate a GRPR/alphaV beta3 dual targeting bivalent ligand. The first bivalent ligand, [RGD-Glu-(NO2A)-6-Ahx-RM2], was synthesized, purified via RP-HPLC, characterized via ESI-MS, and then metallated with nat/64Cu. The natCu-metallated ligand was evaluated in vitro via competitive displacement binding assays (IC50 = 3.09 +/- 0.34 nM in PC-3 cells, IC50 = 518 +/- 37.5 nM in U87-MG cells). In vivo biodistribution studies of [RGD-Glu-( 64Cu-NO2A)-6-Ahx-RM2] were conducted in normal CF-1 mice and PC-3 tumor-bearing SCID mice. The results showed high tumor uptake and retention in PC-3 tumor-bearing SCID mice (4.86 +/- 1.01 %ID/g at 1 h p.i., 4.26 +/- 1.23 %ID/g at 24 h p.i.). High contrast microPET images of the tracer in PC-3 tumor-bearing mice were obtained at 4 h p.i., indicating the strong capability of the tracer to target PC-3 tumor cells in vivo..
520 $a The second bivalent ligand for GRPR/alphaVbeta3 dual targeting , [RGD-Glu-(DO3A)-6-Ahx-RM2] was synthesized, purified by RP-HPLC, characterized with ESI-MS, and metallated with nat/67/68Ga or nat/64Cu. The in vitro investigations of the binding affinities of the natural-metallated ligands for the GRPR or the alpha Vbeta3 integrin were performed via competitive displacement binding assays in human prostate PC-3 and glioblastoma U87-MG cell lines. Following stability investigations via RP-HPLC, the in vivo evaluations of the Ga67/Cu64-radiolabeled ligands were performed in CF-1 mice and SCID mice bearing PC-3 tumors. The in vitro studies of the natural-metallated ligands showed high binding affinities for the GRPR (7.78 +/- 2.42, 8.64 +/- 2.16 nM; Ga, Cu respectively) and moderate binding affinity for the alphaVbeta 3 integrin receptor (307 +/- 0.0, 308 +/- 42.6 nM; Ga, Cu respectively). In vivo biodistribution studies displayed high tumor uptake (7.44 +/- 1.09, 10.85 +/- 4.02%ID/g at 1 h post-intravenous injection; 67Ga, 64Cu respectively) and prolonged tumor retention (4.89 +/- 1.11, 4.09 +/- 0.96%ID/g at 24 h post-intravenous injection; 67Ga, 64Cu respectively) in PC-3 tumor-bearing mice. Micro-single photon emission computed tomography (microSPECT) and micro-positron emission computed tomography (microPET) molecular imaging studies produced high-quality, high-contrast images in PC-3 tumor-bearing mice at 18 h post-intravenous injection. Both radiolabeled ligands shows satisfactory tumor uptake and retention in PC-3 tumor-bearing mice. However, [RGD-Glu-( 67Ga-DO3A)-6-Ahx-RM2] demonstrates superior pharmacokinetic profiles to [RGD-Glu-(64Cu-DO3A)-6-Ahx-RM2], presumably due to more favorable in vivo stability. The comparative studies on [RGD-Glu-( 64Cu/67Ga-DO3A)-6-Ahx-RM2] demonstrated poor in vivo stability of 64Cu-labeled DOTA conjugate and favorable pharmacokinetics of the 67Ga-labeled tracer. As a result, superior in vivo behaviors of [RGD-Glu-(68 Ga-DO3A)-6-Ahx-RM2] are expected for future studies. (Abstract shortened by ProQuest.).
590 $a School code: 0133.
650 4 $a Biochemistry. $3 518028
650 4 $a Oncology. $3 751006
650 4 $a Medical imaging. $3 3172799
690 $a 0487
690 $a 0992
690 $a 0574
710 2 $a University of Missouri - Columbia. $3 1017522
773 0 $t Dissertation Abstracts International $g 78-03B(E).
790 $a 0133
791 $a Ph.D.
792 $a 2015
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10180818