- A Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper-64 with High Tumor Uptake and Retention
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Molecules containing lysine-ureido-glutamate functional groups bind to the active site of prostate specific membrane antigen, which is overexpressed in prostate cancer. To prepare copper radiopharmaceuticals for the diagnosis and therapy of prostate cancer, macrobicyclic sarcophagine ligands tethered to either one or two lysine-ureido-glutamate functional groups through an appropriate linker have been prepared. Sarcophagine ligands can be readily radiolabeled with positron-emitting copper-64 at room temperature. The bivalent agent, in which two targeting groups are tethered to a single copper complex, dramatically outperforms the monomeric agent with respect to tumor uptake and retention. The high tumor uptake, low background, and prolonged tumor retention, even at 24 hours post injection, suggest the bivalent agent is a promising diagnostic for prostate cancer and could be used for prospective dosimetry for therapy with a copper-67 variant.
- Zia, Nicholas A.,Cullinane, Carleen,Van Zuylekom, Jessica K.,Waldeck, Kelly,McInnes, Lachlan E.,Buncic, Gojko,Haskali, Mohammad B.,Roselt, Peter D.,Hicks, Rodney J.,Donnelly, Paul S.
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Read Online
- Two is better than one: Difunctional high-affinity PSMA probes based on a [CpM(CO)3] (M = Re/99mTc) scaffold
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More than 10% of all men will be given the diagnosis "prostate cancer" during their lifetime. Most of the current radio-diagnostic vehicles involve both expensive and localized production with cyclotrons as well as the use of bulky chelators for the radiometal. We report the use of a new multifunctional cyclopentadiene (Cp) platform to prepare difunctional and monofunctional, PSMA-targeting rhenium and technetium-99m complexes. The Cp-complexes and the free ligands are prepared by straightforward functionalization with either one or two Lys-urea-Glu (LuG) PSMA binding motifs. Cell binding assays revealed that the difunctional rhenium complex displays a dissociation constant (KD = 2.1 nM) that is an order of magnitude lower than the monofunctional compound (KD = 24.2 nM). The 99mTc complexes can be prepared in one step and ≤15 min in high yields. These difunctional Cp-Re(i)/99mTc(i) complexes represent a new class of imaging agents with binding affinities comparable to clinically evaluated compounds. Additionally, this study demonstrates that the Cp-platform can readily be derivatized with amine-containing biomolecules. Extending this work to incorporate both targeting and therapeutic moieties could lead to theranostic systems with Re/99mTc.
- Frei, Angelo,Fischer, Eliane,Childs, Bradley Covington,Holland, Jason P.,Alberto, Roger
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- Chemically synthesized molecules with the targeting and effector functions of antibodies
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This article reports the design, synthesis, and evaluation of a novel class of molecules of intermediate size (approximately 7000 Da), which possess both the targeting and effector functions of antibodies. These compounds-called synthetic antibody mimics targeting prostate cancer (SyAM-Ps)-bind simultaneously to prostate-specific membrane antigen and Fc gamma receptor I, thus eliciting highly selective cancer cell phagocytosis. SyAMs have the potential to combine the advantages of both small-molecule and biologic therapies, and may address many drawbacks associated with available treatments for cancer and other diseases.
- McEnaney, Patrick J.,Fitzgerald, Kelly J.,Zhang, Andrew X.,Douglass, Eugene F.,Shan, Weifang,Balog, Aaron,Kolesnikova, Mariya D.,Spiegel, David A.
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- Design and synthesis of a novel BODIPY-labeled PSMA inhibitor
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Prostate-specific membrane antigen (PSMA) is a zinc-bound metalloprotease which is highly expressed in metastatic prostate cancer. It has been considered an excellent target protein for prostate cancer imaging and targeted therapy because it is a membrane protein and its active site is located in the extracellular region. We successfully synthesized and evaluated a novel PSMA ligand conjugated with BODIPY650/665. Compound 1 showed strong PSMA-inhibitory activity and selective uptake into PSMA-expressing tumors. Compound 1 has the potential to be utilized as a near infrared (NIR) optical imaging probe targeting PSMA-expressing cancers.
- Ahn, Hye-Hyun,Byun, Youngjoo,Choi, Doyoung,Ha, Hyunsoo,Kim, Kyul,Kwon, Hongmok,Minn, Il,Nam, Hwanhee,Nam, SangJin,Son, Sang-Hyun
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Read Online
- Synthesis and automated fluorine-18 radiolabeling of new PSMA-617 derivatives with a CuAAC radiosynthetic approach
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In the last decade, the development of new radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research, especially focusing on the prostate-specific membrane antigen (PSMA), an antigen which
- Iannone, Marco N.,Stucchi, Stefano,Turolla, Elia A.,Beretta, Chiara,Ciceri, Samuele,Chinello, Clizia,Pagani, Lisa,Todde, Sergio,Ferraboschi, Patrizia
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- Prostate-specific membrane antigen (PSMA) targeted singlet oxygen delivery via endoperoxide tethered ligands
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Singlet oxygen is the primary agent responsible for the therapeutic effects of photodynamic therapy (PDT). In this work, we demonstrate that singlet oxygen release due to thermal endoperoxide cycloreversion can be targeted towards specific features of sel
- Akkaya, Engin U.,Li, Jin,Liu, Yingjie,Liu, Ziang,Pan, Yue,Tang, Lei,Wang, Lei,Wu, Hao
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supporting information
p. 1902 - 1905
(2022/02/21)
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- PSMA TARGETING UREA-BASED LIGANDS FOR PROSTATE CANCER RADIOTHERAPY AND IMAGING
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The present invention provides novel PSMA targeting urea-based ligands that bind to prostate-specific membrane antigen (PSMA) which is expressed 8-to-12-fold higher in prostate cancer cells when compared to healthy tissue. The PSMA targeting urea-based li
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- COVALENT IMMUNE RECRUITER COMPOUNDS FOR IMMUNE CELL RECOGNITION AND ASSOCIATED USES
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The present application relates to compounds of Formula I comprising an antibody binding domain (ABD) comprising a hapten that binds to an antibody in a subject, the antibody comprising a hapten binding site, an antibody labelling domain (ALD) comprising a functional group that forms a covalent bond with an amino acid in the antibody that is proximal to the hapten binding site and the formation of the covalent bond results in elimination of the ABD and either a target binding domain (TBD) or a detection moiety domain (DMD), each domain being optionally connected with independently selected linkers. The present application also includes methods and uses of the compounds, for example, for immune recognition of target cells by recruited labelled antibodies. [in-line-formulae]ABD?(L1)n-ALD-(L2)m-R[/in-line-formulae]
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- CONJUGATE OF FLUORESCENT DYE FOR THE VISUALIZATION OF PSMA EXPRESSING CELLS
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The invention relates to the field of organic and medicinal chemistry, as well as molecular biology, and concerns a new class of compounds for imaging PSMA expressing cells and tissues, such as prostate cancer cells. New diagnostic conjugates for the visu
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- Synthesis and Biological Evaluation of PSMA Ligands with Aromatic Residues and Fluorescent Conjugates Based on Them
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Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), is a suitable target for specific delivery of antitumor drugs and diagnostic agents due to its overexpression in prostate cancer cells. In the current work, we describe the design, synthesis, and biological evaluation of novel low-molecular PSMA ligands and conjugates with fluorescent dyes FAM-5, SulfoCy5, and SulfoCy7. In vitro evaluation of synthesized PSMA ligands on the activity of PSMA shows that the addition of aromatic amino acids into a linker structure leads to a significant increase in inhibition. The conjugates of the most potent ligand with FAM-5 as well as SulfoCy5 demonstrated high affinities to PSMA-expressing tumor cells in vitro. In vivo biodistribution in 22Rv1 xenografts in Balb/c nude mice of PSMA-SulfoCy5 and PSMA-SulfoCy7 conjugates with a novel PSMA ligand demonstrated good visualization of PSMA-expressing tumors. Also, the conjugate PSMA-SulfoCy7 demonstrated the absence of any explicit toxicity up to 87.9 mg/kg.
- Machulkin, Aleksei E.,Shafikov, Radik R.,Uspenskaya, Anastasia A.,Petrov, Stanislav A.,Ber, Anton P.,Skvortsov, Dmitry A.,Nimenko, Ekaterina A.,Zyk, Nikolay U.,Smirnova, Galina B.,Pokrovsky, Vadim S.,Abakumov, Maxim A.,Saltykova, Irina V.,Akhmirov, Rauf T.,Garanina, Anastasiia S.,Polshakov, Vladimir I.,Saveliev, Oleg Y.,Ivanenkov, Yan A.,Aladinskaya, Anastasiya V.,Finko, Alexander V.,Yamansarov, Emil U.,Krasnovskaya, Olga O.,Erofeev, Alexander S.,Gorelkin, Petr V.,Dontsova, Olga A.,Beloglazkina, Elena K.,Zyk, Nikolay V.,Khazanova, Elena S.,Majouga, Alexander G.
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p. 4532 - 4552
(2021/05/06)
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- TARGETED RADIOPHARMACEUTICALS FOR THE DIAGNOSIS AND TREATMENT OF PROSTATE CANCER
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A compound of general formula (I): wherein: n is 1, 2 or 3; R1, R2, R3 and R4, independently represent OH or Q; and 20 Q represents a tissue-targeting moeity selected from the group consisting of or a stereoisomer, a hydrate, a solvate, or a salt thereof, or a mixture of same, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said 25 compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of soft tissue diseases, as a sole agent or in combination with other active ingredients.
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- CONJUGATE MONOMETHYL AURISTATIN E TO OBTAIN A COMPOSITION FOR TREATMENT OF PROSTATE CANCER
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?This invention is the conjugate of formula (I) for treatment of tumors expressing PSMA, including PSMA-ligand with linker and antineoplastic agent MMAE, the composition for lyophilizate preparation based on it, the dosage form for therapy and obtained by
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- Synthesis and Preclinical Evaluation of [18F]SiFA-PSMA Inhibitors in a Prostate Cancer Model
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Positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA) with gallium-68 (68Ga) and fluorine-18 (18F) radiotracers has aroused tremendous interest over the past few years. The use of organosilicon-[18F]fluoride acceptors (Si
- Bailey, Justin J.,Bhardwaj, Atul,Schirrmacher, Ralf,Valliant, John F.,W?ngler, Bjoern,W?ngler, Carmen,Wagner, Michael,Wuest, Frank,Wuest, Melinda
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p. 15671 - 15689
(2021/11/13)
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- Hybrid chelator-based PSMA radiopharmaceuticals: Translational approach
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(1) Background: Prostate-specific membrane antigen (PSMA) has been extensively studied in the last decade. It became a promising biological target in the diagnosis and therapy of PSMAexpressing cancer diseases. Although there are several radiolabeled PSMA
- Greifenstein, Lukas,Grus, Tilmann,Lahnif, Hanane,Pektor, Stefanie,R?sch, Frank,Schreckenberger, Mathias
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- PSMA inhibitor, application thereof and PSMA-targeting nuclide imaging reagent
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The invention belongs to the technical field of biological medicines, and particularly relates to a PSMA inhibitor, an application thereof and a PSMA-targeting nuclide imaging reagent. The PSMA inhibitor has a structure as shown in a formula I. The PSMA-targeting nuclide imaging reagent prepared by adopting EDDA as a co-ligand has good PSMA targeting property and affinity; high stability is realized in normal saline and mouse serum; meanwhile, the cell uptake amount is relatively high, and the metabolic performance is good. Therefore, the inhibitor has a good clinical application prospect in tumor imaging of targeted PSMA.
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Paragraph 0065; 0066; 0067
(2020/06/20)
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- Modular Medical Imaging Agents Based on Azide–Alkyne Huisgen Cycloadditions: Synthesis and Pre-Clinical Evaluation of 18F-Labeled PSMA-Tracers for Prostate Cancer Imaging
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Since the seminal contribution of Rolf Huisgen to develop the [3+2] cycloaddition of 1,3-dipolar compounds, its azide–alkyne variant has established itself as the key step in numerous organic syntheses and bioorthogonal processes in materials science and chemical biology. In the present study, the copper(I)-catalyzed azide–alkyne cycloaddition was applied for the development of a modular molecular platform for medical imaging of the prostate-specific membrane antigen (PSMA), using positron emission tomography. This process is shown from molecular design, through synthesis automation and in vitro studies, all the way to pre-clinical in vivo evaluation of fluorine-18- labeled PSMA-targeting ‘F-PSMA-MIC’ radiotracers (t1/2=109.7 min). Pre-clinical data indicate that the modular PSMA-scaffold has similar binding affinity and imaging properties to the clinically used [68Ga]PSMA-11. Furthermore, we demonstrated that targeting the arene-binding in PSMA, facilitated through the [3+2]cycloaddition, can improve binding affinity, which was rationalized by molecular modeling. The here presented PSMA-binding scaffold potentially facilitates easy coupling to other medical imaging moieties, enabling future developments of new modular imaging agents.
- B?hmer, Verena I.,Szymanski, Wiktor,van den Berg, Keimpe-Oeds,Mulder, Chantal,Kobauri, Piermichele,Helbert, Hugo,van der Born, Dion,Reeβing, Friederike,Huizing, Anja,Klopstra, Marten,Samplonius, Douwe F.,Antunes, Ines F.,Sijbesma, Jürgen W. A.,Luurtsema, Gert,Helfrich, Wijnand,Visser, Ton J.,Feringa, Ben L.,Elsinga, Philip H.
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p. 10871 - 10881
(2020/07/25)
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- Synthesis of a porphyrin with histidine-like chelate: an efficient path towards molecular PDT/SPECT theranostics
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The goal of “personalised” medicine has seen a growing interest in the development of theranostic agents. Bifunctional, and targeted-trifunctional, theranostic water-soluble porphyrins with a histidine-like chelating group have been synthesisedviacopper-catalysed azide-alkyne cycloaddition (CuAAC) “click” chemistry in high yield and purity. They are capable of photodynamic treatment and [99mTc(CO)3]+complexation for single-photon emission computed tomography (SPECT) imaging, with a radiochemical yield of >95%. The toxicity and phototoxicity were evaluated on HT-29 cells, DU145, and DU145-PSMA cell lines, with the targeted theranostic showing more potent phototoxicity towards DU145-PSMA expressing cells.
- Yap, Steven Y.,Savoie, Huguette,Renard, Isaline,Burke, Benjamin P.,Sample, Harry C.,Michue-Seijas, Saul,Archibald, Stephen J.,Boyle, Ross W.,Stasiuk, Graeme J.
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p. 11090 - 11093
(2020/10/05)
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- Design, synthesis, computational, and preclinical evaluation of Natti/45Ti-labeled urea-based glutamate PSMA ligand
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Despite promising anti-cancer properties in vitro, all titanium-based pharmaceuticals have failed in vivo. Likewise, no target-specific positron emission tomography (PET) tracer based on the radionuclide 45Ti has been developed, notwithstanding its excellent PET imaging properties. In this contribution, we present liquid–liquid extraction (LLE) in flow-based recovery and the purification of 45Ti, computer-aided design, and the synthesis of a salan-natTi/45Ti-chelidamic acid (CA)-prostate-specific membrane antigen (PSMA) ligand containing the Glu-urea-Lys pharmacophore. The compound showed compromised serum stability, however, no visible PET signal from the PC3+ tumor was seen, while the ex vivo biodistribution measured the tumor accumulation at 1.1% ID/g. The in vivo instability was rationalized in terms of competitive citrate binding followed by Fe(III) transchelation. The strategy to improve the in vivo stability by implementing a unimolecular ligand design is presented.
- Baun, Christina,Jensen, Andreas Ingemann,Nielsen, Karin Michaelsen,Pedersen, Kristina S?borg,Thisgaard, Helge,Zhuravlev, Fedor
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- IMAGING AGENTS
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This invention relates to compounds of formula I or la: Y1 is -EuK, -EuFA, -EuPG, -L1-EuK, -L1-EuFA, -L1-EuPG or -L3-EuE; Y2 is -L4-EuK, - L4-EuFA, - L4-EuPG, -EuE, or -L2-EuE; Z is a chelating moiety; and the other substituents are as defined herein. Also provided are formulations comprising such a compound, as well as methods of imaging or methods for the treatment of cancer comprising use of such a compound or formulation.
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- Polypeptide-based molecular platform and its docetaxel/sulfo-cy5-containing conjugate for targeted delivery to prostate specific membrane antigen
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A strategy for stereoselective synthesis of molecular platform for targeted delivery of bimodal therapeutic or theranostic agents to the prostate-specific membrane antigen (PSMA) receptor was developed. The proposed platform contains a urea-based, PSMA-targeting Glu-Urea-Lys (EuK) fragment as a vector moiety and tripeptide linker with terminal amide and azide groups for subsequent addition of two different therapeutic and diagnostic agents. The optimal method for this molecular platform synthesis includes (a) solid-phase assembly of the polypeptide linker, (b) coupling of this linker with the vector fragment, (c) attachment of 3-aminopropylazide, and (d) amide and carboxylic groups deprotection. A bimodal theranostic conjugate of the proposed platform with a cytostatic drug (docetaxel) and a fluorescent label (Sulfo-Cy5) was synthesized to demonstrate its possible sequential conjugation with different functional molecules.
- Beloglazkina, Elena K.,Garanina, Anastasia S.,Grishin, Yuri K.,Machulkin, Aleksei E.,Majouga, Alexander G.,Nimenko, Ekaterina A.,Petrov, Rostislav A.,Petrov, Stanislav A.,Polshakov, Vladimir I.,Roznyatovsky, Vitaly A.,Uspenskaya, Anastasia A.,Zyk, Nikolay V.,Zyk, Nikolay Y.
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- Preparation and biological evaluation of [99m Tc]Tc-CNGU as a PSMA-targeted radiotracer for the imaging of prostate cancer
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Prostate-specific membrane antigen (PSMA) is a well-established biological target that is overexpressed on the surface of prostate cancer lesions. Radionuclide-labeled small-molecule PSMA inhibitors have been shown to be promising PSMA-specific agents for the diagnosis and therapy of prostate cancer. In this study, a glutamate-urea-based PSMA-targeted ligand containing an isonitrile (CNGU) was synthesized and labeled with99m Tc to prepare [99m Tc]Tc-CNGU with a high radiochemical purity (RCP). The CNGU ligand showed a high affinity toward PSMA (Ki value is 8.79 nM) in LNCaP cells. The [99m Tc]Tc-CNGU exhibited a good stability in vitro and hydrophilicity (log P = ?1.97 ± 0.03). In biodistribution studies, BALB/c nude mice bearing LNCaP xenografts showed that the complex had a high tumor uptake with 4.86 ± 1.19% ID/g, which decreased to 1.74 ± 0.90% ID/g after a pre-injection of the selective PSMA inhibitor ZJ-43, suggesting that it was a PSMA-specific agent. Micro-SPECT imaging demonstrated that the [99m Tc]Tc-CNGU had a tumor uptake and that the uptake was reduced in the image after blocking with ZJ-43, further confirming its PSMA specificity. All of the results in this work indicated that [99m Tc]Tc-CNGU is a promising PSMA-specific tracer for the imaging of prostate cancer.
- Duan, Xiaojiang,Gan, Qianqian,Xiao, Di,Zhang, Junbo,Zhang, Xuran
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- Prostate specific membrane antigen inhibitor, metal marker thereof, preparation method and application
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The invention discloses a prostate specific membrane antigen inhibitor, a metal marker, a preparation method and application thereof, and belongs to the technical field of biological medicines. The structure of the prostate specific membrane antigen inhib
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- SILICON-FLUORIDE ACCEPTOR SUBSTITUTED RADIOPHARMACEUTICALS AND PRECURSORS THEREOF
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A ligand-SiFA conjugate compound represented by formula (1) wherein: RL is a ligand moiety which is capable of binding to prostate-specific membrane antigen (PSMA); RSiFA is a silicon-fluoride acceptor (SiFA) moiety which can be labe
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- PSMA-TARGETING AMANITIN CONJUGATES
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The invention relates to a PSMA-targeting conjugate comprising (a) an amatoxin; (b) a small molecule PSMA-targeting moiety; and (c) optionally a linker linking said amatoxin and said small molecule PSMA-targeting moiety. The invention furthermore relates to a pharmaceutical composition comprising such conjugate.
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- Enzymatic radiosynthesis of a18F-Glu-Ureido-Lys ligand for the prostate-specific membrane antigen (PSMA)
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Prostate cancer represents a major public health threat as it is one of the most common male cancers worldwide. The prostate-specific membrane antigen (PSMA) is highly over-expressed in prostatic cancer cells in a manner that correlates with both tumour s
- Lowe, Phillip T.,Dall'Angelo, Sergio,Fleming, Ian N.,Piras, Monica,Zanda, Matteo,O'Hagan, David
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p. 1480 - 1486
(2019/02/14)
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- Synthesis and biological evaluation of Doxorubicin-containing conjugate targeting PSMA
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Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), has recently emerged as a prominent biomarker of prostate cancer (PC) and as an attractive protein trap for drug targeting. At the present time, several drugs and molecular diagnostic tools conjugated with selective PSMA ligands are actively evaluated in different preclinical and clinical trials. In the current work, we discuss design, synthesis and a preliminary biological evaluation of PSMA-specific small-molecule carrier equipped by Doxorubicin (Dox). We have introduced an unstable azo-linker between Dox and the carrier hence the designed compound does release the active substance inside cancer cells thereby providing a relatively high Dox concentration in nuclei and a relevant cytotoxic effect. In contrast, we have also synthesized a similar conjugate with a stable amide linker and it did not release the drug at all. This compound was predominantly accumulated in cytoplasm and did not cause cell death. Preliminary in vivo evaluation has showed good efficiency for the degradable conjugate against PC3-PIP(PSMA+)-containing xenograft mine. Thus, we have demonstrated that the conjugate can be used as a template to design novel analogues with improved targeting, anticancer activity and lower rate of potential side effects. 3D molecular docking study has also been performed to elucidate the underlying mechanism of binding and to further optimization of the linker area for improving the target affinity.
- Ivanenkov, Yan A.,Machulkin, Alexey E.,Garanina, Anastasia S.,Skvortsov, Dmitry A.,Uspenskaya, Anastasia A.,Deyneka, Ekaterina V.,Trofimenko, Alexander V.,Beloglazkina, Elena K.,Zyk, Nikolay V.,Koteliansky, Victor E,Bezrukov, Dmitry S.,Aladinskaya, Anastasia V.,Vorobyeva, Nataliya S.,Puchinina, Maria M.,Riabykh, Grigory K.,Sofronova, Alina A.,Malyshev, Alexander S.,Majouga, Alexander G.
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p. 1246 - 1255
(2019/03/26)
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- Synthesis and biological evaluation of PSMA-targeting paclitaxel conjugates
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Prostate cancer (PC) is the second most commonly occurring cancer in men. Conventional chemotherapy has wide variety of disadvantages such as high systemic toxicity and low selectivity. Targeted drug delivery is a promising approach to decrease side effec
- Machulkin, Alexey E.,Skvortsov, Dmitry A.,Ivanenkov,Ber, Anton P.,Kavalchuk, Mikhail V.,Aladinskaya, Anastasia V.,Uspenskaya, Anastasia A.,Shafikov, Radik R.,Plotnikova, Ekaterina A.,Yakubovskaya, Raisa I.,Nimenko, Ekaterina A.,Zyk, Nikolay U.,Beloglazkina, Elena K.,Zyk, Nikolay V.,Koteliansky, Victor E,Majouga, Alexander G.
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p. 2229 - 2235
(2019/06/27)
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- 18F-LABELED PEPTIDE LIGANDS USEFUL IN PET AND CERENKOV LUMINESCENE IMAGING
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The present technology is directed to compounds, intermediates thereof, compositions thereof, medicaments thereof, and methods related to the imaging of mammalian tissue via 18F- labeled peptide ligands disclosed herein.
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- PSMA LIGANDS FOR IMAGING AND ENDORADIOTHERAPY
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The present disclosure relates to imaging and endoradiotherapy of diseases involving prostate-specific membrane antigen (PSMA). Provided are compounds which bind or inhibit PSMA and furthermore carry at least one moiety which is amenable to radiolabeling.
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- SMALL MOLECULE ADAPTER REGULATED
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In one embodiment, the invention' provides a chimeric antigen receptor (CAR) T cell which is conjugated to a bi-functional molecule which is specific for both an extracellular binding domain of the chimeric antigen receptor (CAR) T cell and prostate-speci
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- RADIOPHARMACEUTICALS, RADIOIMAGING AGENTS, AND USES THEREOF
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The present invention relates to compounds that are useful as radiopharmaceuticals and radioimaging agents which bear a radionuclide-chelating agent. These coordinated compounds are useful in radiotherapy and diagnostic imaging. The invention also relates to methods of diagnosis, prognosis and therapy utilising the non-coordinated and radiolabelled compounds of the invention.
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Page/Page column 29
(2019/01/06)
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- Synthesis of PSMA-targeted 131- and 152-substituted chlorin e6 derivatives and their biological properties
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Prostate cancer is an extremely common cancer among older men. Conventional chemotherapy has proven to be not effective enough in battling it due to its high systemic toxicity and low selectivity. An alternative method of cancer treatment known as photodynamic therapy (PDT) has been shown to be effective. It is not without its faults either: one of the issues it's been known to have is the insufficient selectivity of photosensitizer accumulation in tumor tissues. Recent studies, however, seem to indicate that introducing a PSMA-targeted moiety into photosensitizer might prove to be a solution to this problem. The present paper is concerned with synthesis of PSMA-targeted 131- and 152-substituted chlorin e6 conjugates and their biological characteristics. Our data suggests that the developed conjugates show potential as targeted agents for photodynamic therapy.
- Suvorov, Nikita V.,MacHulkin, Alexey E.,Ivanova, Anna V.,Popkov, Alexander M.,Bondareva, Elizaveta A.,Plotnikova, Ekaterina A.,Yakubovskaya, Raisa I.,Majouga, Alexander G.,Mironov, Andrey F.,Grin, Mikhail A.
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p. 1030 - 1038
(2018/09/29)
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- METHODS OF TREATING CANCER WITH A PSMA LIGAND-TUBULYSIN COMPOUND
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The invention described herein pertains to drug delivery conjugates for targeted therapy. The invention described herein relates to methods of treating PSMA expressing cancers with a PSMA ligand-tubulysin compound. The invention described herein also relates to methods of treating PSMA-expressing cancers with a PSMA ligand-tubulysin compound in patients where stable disease results after treatment with the PSMA ligand-tubulysin compound.
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- ERG TARGETED THERAPY
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The present disclosure relates to compositions and methods for cancer therapy, including but not limited to, targeted inhibition of cancer markers. In particular, the present disclosure relates to recurrent gene fusions as clinical targets for cancer.
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- POLYNUCLEOTIDE CONSTRUCTS
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Disclosed are polynucleotide constructs having a strand linked to a moiety carrying one or more auxiliary moieties. Also disclosed are polynucleotide constructs interrupted with a sugar analogue, and polynucleotide constructs with stereochemical^ enriched phosphorothioates. The polynucleotide constructs may be provided as hybridized polynucleotide constructs. Also featured are methods of delivery a polynucleotide construct to a cell and methods of reducing the expression of a protein in a cell by contacting the cell with the disclosed polynucleotide construct or hybridized polynucleotide construct.
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- Development of a Ga-68 labeled PET tracer with short linker for prostate-specific membrane antigen (PSMA) targeting
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Glu-Urea-Lys (GUL) derivatives have been reported as prostate-specific membrane antigen (PSMA) agent. We developed derivatives of GUL conjugated with NOTA or DOTA via a thiourea linker and tested their feasibility as PSMA imaging agents after labeling wit
- Moon, Sung-Hyun,Hong, Mee Kyung,Kim, Young Ju,Lee, Yun-Sang,Lee, Dong Soo,Chung, June-Key,Jeong, Jae Min
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p. 2501 - 2507
(2018/04/17)
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- The efficiency of 18F labelling of a prostate specific membrane antigen ligand via strain-promoted azide-alkyne reaction: reaction speed versus hydrophilicity
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Here we report the 18F labeling of a prostate specific membrane antigen (PSMA) ligand via a strain promoted oxa-dibenzocyclooctyne (ODIBO)- or bicyclo[6.1.0]nonyne (BCN)-azide reaction. Although ODIBO reacts with azide 20 fold faster than BCN, in vivo PET imaging suggests that 18F-BCN-azide-PSMA demonstrated much higher tumor uptake and a much higher tumor to background contrast.
- Wang, Mengzhe,McNitt, Christopher D.,Wang, Hui,Ma, Xiaofen,Scarry, Sarah M.,Wu, Zhanhong,Popik, Vladimir V.,Li, Zibo
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supporting information
p. 7810 - 7813
(2018/07/25)
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- DOUBLE TARGETED CONSTRUCTS TO AFFECT TUMOR KILL
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The present technology is directed to compounds, compositions, medicaments, and methods related to the treatment of cancers expressing PSMA. The compounds are of Formulas I and II or pharmaceutically acceptable salts thereof. The present technology is especially well-suited for use in treating prostate cancer.
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- 18/19F-LABELLED COMPOUNDS WHICH TARGET THE PROSTATE SPECIFIC MEMBRANE ANTIGEN
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This disclosure relates to novel compounds comprising a zwitterionic trifluoroborate prosthetic group which target prostate-specific membrane antigen (PSMA), e.g. in prostate cancer. The compounds have Formula I, wherein each Rl is an anionic group, L is
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- METHODS OF TREATING CANCER WITH A PSMA LIGAND-TUBULYSIN COMPOUND
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The invention described herein pertains to drug delivery conjugates for targeted therapy. The invention described herein relates to methods of treating PSMA expressing cancers with a PSMA ligand-tubulysin compound. The invention described herein also relates to methods of treating PSMA-expressing cancers with a PSMA ligand-tubulysin compound in patients where stable disease results after treatment with the PSMA ligand-tubulysin compound.
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- 18F-LABELED TRIAZOLE CONTAINING PSMA INHIBITORS
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The present technology is directed to compounds, intermediates thereof, compositions thereof, medicaments thereof, and methods related to the imaging of mammalian tissue overexpressing PSMA. The compounds are of Formula I or a pharmaceutically acceptable salt thereof, wherein one of R1, R2, and R3 is and of Formula IV or a pharmaceutically acceptable salt thereof.
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- 99mTc Radiolabeling and Biological Evaluation of Nanoparticles Functionalized with a Versatile Coating Ligand
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Radiolabeling allows noninvasive imaging by single photon emission computed tomography (SPECT) or positron emission tomography (PET) for assessing the biodistribution of nanostructures. Herein, the synthesis of a new coating ligand for gold nanoparticles (AuNPs) and quantum dots (QDs) is reported. This ligand is multifunctional; it combines the metal chelate with conjugating functions to biological vectors. The concept allows the coupling of any targeting function to the chelator; an example for the prostate specific membrane antigen is given. Derivatized NPs can directly be labeled in one step with [99mTc(OH2)3(CO)3]+. AuNPs in particular are highly stable, a prerequisite for in vivo studies excluding misinterpretation of the biodistribution data. AuNPs with differing sizes (7 and 14 nm core diameter) were administered intravenously into nude NMRI mice bearing LNCaP xenografts. MicroSPECT images show for both probes rapid clearance from the blood pool through the hepatobiliary pathway. The 7 nm AuNPs revealed a significantly higher bone uptake than the 14 nm AuNPs. The high affinity towards bone mineral is further confirmed in vitro with hydroxyapatite.
- Felber, Michael,Bauwens, Matthias,Mateos, José M.,Imstepf, Sebastian,Mottaghy, Felix M.,Alberto, Roger
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p. 6090 - 6099
(2015/04/14)
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- POLYNUCLEOTIDE CONSTRUCTS HAVING DISULFIDE GROUPS
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The invention features polynucleotide constructs containing one or more components (i) containing a disulfide linkage, where each of the one or more components is attached to an internudeotide bridging group or a terminal group of the polynucleotide construct, and each of the one or more components (i) contains one or more bulky groups proximal to the disulfide group. The invention also features polynucleotide constructs containing one or more components (i) containing a disulfide linkage, where each of the one or more components (i) is attached to an internudeotide bridging group or a terminal group of the polynucleotide construct, and each of the one or more components (i) contains at least 4 atoms in a chain between the disulfide linkage and the phosphorus atom of the internudeotide bridging group or the terminal group; and where the chain does not contain a phosphate, an amide, an ester, or an alkenylene. The invention also features methods of delivering a polynucleotide to a cell using the polynucleotide constructs of the invention.
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- POLYNUCLEOTIDE CONSTRUCTS HAVING BIOREVERSIBLE AND NON-BIOREVERSIBLE GROUPS
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The invention features a hybridized polynucleotide construct containing a passenger strand, a guide strand loadable into a RISC complex, and (i) a 3'-terminal or an internucleotide non-bioreversible group in the guide strand; or (ii) a 5'-terminal, a 3'-terminal, or an internucleotide non-bioreversible group in the passenger strand, and a 5'-terminal, a 3'-terminal, or an internucleotide disulfide bioreversible group in the guide strand or the passenger strand. The invention also features methods of delivering a polynucleotide to a cell using the hybridized polynucleotide construct. The invention further features methods of reducing the expression of a polypeptide in a cell using the hybridized polynucleotide construct.
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- TARGETING AGENT ANTIBODY CONJUGATES AND USES THEREOF
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Methods, compositions and uses are provided for bispecific antibodies comprising one or more unnatural amino acids. The bispecific antibodies may bind to two or more different receptors, co- receptors, antigens, or cell markers on one or more cells. The b
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Paragraph 00342; 00345; 00346
(2014/10/04)
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- CONJUGATES FOR TREATING DISEASES CAUSED BY PSMA EXPRESSING CELLS
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The invention described herein pertains to the diagnosis, imaging, and/or treatment of pathogenic cell populations. In particular, the invention described herein pertains to the diagnosis, imaging, and/or treatment of diseases caused by PSMA expressing cells, such as prostate cancer cells, using compounds capable of targeting PSMA expressing cells.
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- TLR-AGONIST-CONJUGATED ANTIBODY RECRUITING MOLECULES (TLR_ARMS)
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The present invention relates to chimeric chemical compounds which are used to recruit antibodies to cancer cells, in particular, prostate cancer cells or metastasized prostate cancer cells. The compounds according to the present invention comprise an antibody binding terminus (ABT) moiety covalently bonded to a cell binding terminus (CBT) and Toll-like receptor agonist (TLR) through a linker and a multifunctional connector group or molecule.
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- CHIMERIC SMALL MOLECULES FOR THE RECRUITMENT OF ANTIBODIES TO CANCER CELLS
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The present invention relates to chimeric chemical compounds which are used to recruit antibodies to cancer cells, in particular, prostate cancer cells or metastasized prostate cancer cells. The compounds according to the present invention comprise an ant
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- Chemical control over immune recognition: A class of antibody-recruiting small molecules that target prostate cancer
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(Figure Presented) Prostate cancer is the second leading cause of cancer-related death among the American male population, and society is in dire need of new approaches to treat this disease. Here we report the design, synthesis, and biological evaluation
- Murelli, Ryan P.,Zhang, Andrew X.,Michel, Julien,Jorgensen, William L.,Spiegel, David A.
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supporting information; experimental part
p. 17090 - 17092
(2010/03/25)
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- HETERODIMERS OF GLUTAMIC ACID
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Compounds of Formula (Ia) wherein R is a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl, a C1-C6 substituted or unsubstituted alkyl or —NR′R′, Q is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)pY is C(O), O, NR′, S, S(O)2, C(O)2 (CH2)p Z is H or C1-C4 alkyl,R′ is H, C(O), S(O)2, C(O)2, a C6-C12 substituted or unsubstituted aryl, a C6-C12 substituted or unsubstituted heteroaryl or a C1-C6 substituted or unsubstituted alkyl, when substituted, aryl, heteroaryl and alkyl are substituted with halogen, C6-C12 heteroaryl, —NR′R′ or COOZ, which have diagnostic and therapeutic properties, such as the treatment and management of prostate cancer and other diseases related to NAALADase inhibition. Radiolabels can be incorporated into the structure through a variety of prosthetic groups attached at the X amino acid side chain via a carbon or hetero atom linkage.
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Page/Page column 6
(2008/12/07)
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