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000179660 1001_ $$0P:(DE-He78)c8c77862236d6e9b311705b9ecdf0413$$aLiolios, Christos$$b0$$eFirst author
000179660 245__ $$aInvestigation of Tumor Cells and Receptor-Ligand Simulation Models for the Development of PET Imaging Probes Targeting PSMA and GRPR and a Possible Crosstalk between the Two Receptors.
000179660 260__ $$aWashington, DC$$bAmerican Chemical Society$$c2022
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000179660 500__ $$a#EA:E030# / 2022 Jul 4;19(7):2231-2247 /  German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
000179660 520__ $$aProstate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) have both been used in nuclear medicine as targets for molecular imaging and therapy of prostate (PCa) and breast cancer (BCa). Three bioconjugate probes, the PSMA specific: [68Ga]Ga-1, ((HBED-CC)-Ahx-Lys-NH-CO-NH Glu or PSMA-11), the GRPR specific: [68Ga]Ga-2, ((HBED-CC)-4-amino-1-carboxymethyl piperidine-[D-Phe6, Sta13]BN(6-14), a bombesin (BN) analogue), and 3 (the BN analogue: 4-amino-1-carboxymethyl piperidine-[(R)-Phe6, Sta13]BN(6-14) connected with the fluorescent dye, BDP-FL), were synthesized and tested in vitro with PCa and BCa cell lines, more specifically, with PCa cells, PC-3 and LNCaP, with BCa cells, T47D, MDA-MB-231, and with the in-house created PSMA-overexpressing PC-3(PSMA), T47D(PSMA), and MDA-MB-231(PSMA). In addition, biomolecular simulations were conducted on the association of 1 and 2 with PSMA and GRPR. The PSMA overexpression resulted in an increase of cell-bound radioligand [68Ga]Ga-1 (PSMA) for PCa and BCa cells and also of [68Ga]Ga-2 (GRPR), especially in those cell lines already expressing GRPR. The results were confirmed by fluorescence-activated cell sorting with a PE-labeled PSMA-specific antibody and the fluorescence tracer 3. The docking calculations and molecular dynamics simulations showed how 1 enters the PSMA funnel region and how pharmacophore Glu-urea-Lys interacts with the arginine patch, the S1', and S1 subpockets by forming hydrogen and van der Waals bonds. The chelating moiety of 1, that is, HBED-CC, forms additional stabilizing hydrogen bonding and van der Waals interactions in the arene-binding site. Ligand 2 is diving into the GRPR transmembrane (TM) helical cavity, thereby forming hydrogen bonds through its amidated end, water-mediated hydrogen bonds, and π-π interactions. Our results provide valuable information regarding the molecular mechanisms involved in the interactions of 1 and 2 with PSMA and GRPR, which might be useful for the diagnostic imaging and therapy of PCa and BCa.
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000179660 650_7 $$2Other$$aGRPR
000179660 650_7 $$2Other$$aLNCaP
000179660 650_7 $$2Other$$aMD simulations
000179660 650_7 $$2Other$$aMD-MB231
000179660 650_7 $$2Other$$aPC-3
000179660 650_7 $$2Other$$aPET imaging
000179660 650_7 $$2Other$$aPSMA
000179660 650_7 $$2Other$$aT47D
000179660 650_7 $$2Other$$abreast cancer
000179660 650_7 $$2Other$$aprostate cancer
000179660 7001_ $$0P:(DE-He78)e41ce75a370dda1c81800f1e53d2d12a$$aPatsis, Christos$$b1
000179660 7001_ $$00000-0002-2820-9338$$aLambrinidis, George$$b2
000179660 7001_ $$aTzortzini, Efpraxia$$b3
000179660 7001_ $$0P:(DE-He78)1a25bc9516a97a13551ebd083356d24f$$aRoscher, Mareike$$b4
000179660 7001_ $$0P:(DE-He78)033d979f00729281e709b85fe6cae972$$aBauder-Wüst, Ulrike$$b5
000179660 7001_ $$00000-0001-6110-1903$$aKolocouris, Antonios$$b6
000179660 7001_ $$0P:(DE-He78)9793347ba83f527b81a22ab75af9378a$$aKopka, Klaus$$b7
000179660 773__ $$0PERI:(DE-600)2132489-X$$a10.1021/acs.molpharmaceut.2c00070$$gp. acs.molpharmaceut.2c00070$$n7$$p2231-2247$$tMolecular pharmaceutics$$v19$$x1543-8384$$y2022
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