Radiolabeled iron oxide nanoparticles functionalized with PSMA/BN ligands for dual-targeting of prostate cancer

IntroductionProstate cancer (PCa) is the second most frequent cancer diagnosis in men and the fifth leading cause of death worldwide. Prostate Specific Membrane Antigen (PSMA) and Gastrin Releasing Peptide (GRP) receptors are overexpressed in PCa. In this study, we have developed iron oxide nanoparticles (IONs) functionalized with the Prostate Specific Membrane Antigen (PSMA) and Gastrin Releasing Peptide (GRP) ligands for dual targeting of Prostate cancer.MethodsIONs were developed with a thin silica layer on their surface with MPTES (carrying -SH groups, IONs-SH), and they were coupled either with a pharmacophore targeting PSMA (IONs-PSMA) or with bombesin peptide (IONs-BN), targeting GRP receptors, or with both (IONs-PSMA/BN). The functionalized IONs were characterized for their size, zeta potential, and efficiency of functionalization using dynamic light scattering (DLS) and Fourier-Transform Infrared Spectroscopy (FT-IR). All the aforementioned types of IONs were radiolabeled directly with Technetium-99m (99mTc) and evaluated for their radiolabeling efficiency, stability, and binding ability on two different PCa cell lines (PC3 and LNCaP).Results and DiscussionThe MTT assay demonstrated low toxicity of the IONs against PC3 and LNCaP cells, while the performed wound-healing assay further proved that these nanostructures did not affect cellular growth mechanisms. The observed hemolysis ratio after co-incubation with red blood cells was extremely low. Furthermore, the 99mTc-radiolabeled IONs showed good stability in human serum, DTPA, and histidine, and high specific binding rates in cancer cells, supporting their future utilization as potential diagnostic tools for PCa with Single Photon Emission Computed Tomography (SPECT) imaging

Amantadine variant - aryl conjugates that inhibit multiple M2 mutant - amantadine resistant influenza a viruses

Influenza A viruses can cause a serious future threat due to frequent mutations. Amantadine and rimantadine inhibit influenza A M2 wild-type (WT) viruses by binding and blocking M2 WT channel-mediated proton current. The resistant to the drugs amantadine and rimantadine influenza A viruses bearing the S31 N mutant in the M2 proton channel can be inhibited by amantadine - aryl conjugates, in which amantadine and an aryl group are linked through a methylene, which block M2 S31 N channel-mediated proton current. However, the M2 amantadine/rimantadine resistant viruses bearing one of the four mutations L26F, V27A, A30T, G34E in residues that line the M2 protein pore pose an additional concern for public health. Here, we designed 33 compounds based on the structure of three previously published and potent amantadine-aryl conjugates against M2 S31 N virus, by replacing amantadine with 16 amantadine variants. The compounds were tested against M2 WT and the five M2 amantadine-resistant viruses aiming at identifying inhibitors against multiple M2 mutant - amantadine resistant viruses. We identified 16 compounds that inhibited in vitro two influenza A viruses with M2 WT or L26F channels. Additionally, compounds 21 or 32 or 33, which are conjugates of the rimantadine variant with CMe2 (instead of CHMe in rimantadine) or the diamantylamine or the 4-(1-adamantyl)benzenamine with the 2-hydroxy-4-methoxyphenyl aryl group, were in vitro inhibitors against three influenza A viruses with M2 WT or L26F or S31 N, while compound 21 inhibited also in vitro the M2 G34E virus and 32 inhibited also in vitro the M2 A30T virus. For these compounds we performed a preliminary drug metabolism and pharmacokinetics study. Also, using electrophysiology, we showed that compound 21 was an efficient blocker of the M2 WT and M2 L26F channels, compound 32 blocked efficiently the M2 WT channel and compound 33 blocked the M2 WT, L26F and V27A channels. The drug metabolism and pharmacokinetics studies showed these compounds need further optimization

CAST constraints on the axion-electron coupling

In non-hadronic axion models, which have a tree-level axion-electron interaction, the Sun produces a strong axion flux by bremsstrahlung, Compton scattering, and axiorecombination, the "BCA processes." Based on a new calculation of this flux, including for the first time axio-recombination, we derive limits on the axion-electron Yukawa coupling gae and axion-photon interaction strength ga using the CAST phase-I data (vacuum phase). For ma <~ 10 meV/c2 we find ga gae < 8.1 × 10−23 GeV−1 at 95% CL. We stress that a next-generation axion helioscope such as the proposed IAXO could push this sensitivity into a range beyond stellar energy-loss limits and test the hypothesis that white-dwarf cooling is dominated by axion emission

Chemical Composition and Antimicrobial Activity of the Essential Oil of Algerian Phlomis bovei De Noé subsp. bovei

The chemical composition of essential oil obtained by steam distillation of dried aerial parts of Phlomis bovei De Noé subsp. bovei collected from Algeria, was analyzed by GC and GC/MS. Seventy five constituents (corresponding to 86.37% of the total weight) were identified. The main components were: germacrene D, β-caryophyllene, β-bournonene, thymol and hexahydrofarnesyl acetone. Furthermore, the antimicrobial activity of the oil was evaluated against six Gram (+/-) bacteria and three pathogenic fungi, using the agar dilution technique. It was found that the oil exhibited strong antimicrobial activity against most of the tested microorganisms

Radiochemical, radiopharmacological, biodistribution and pharmacokinetic studies for the development of new bombesin analogues radiolebeled with diagnostic radionuclides for the treatment of cancer

Purpose of the Study: The present Thesis refers to the development of new peptidic bombesin (BN) analogs for application in the field of tumor diagnosis with the SPECT (Single-photon emission computed tomography) and PET (Positron emission tomography) techniques. The BN peptide is a specific ligand for the gastrin-releasing peptide receptors (GRPrs), which are over-expressed on the surface of various types of tumor cells. GRPrs can be considered as an ideal target for radiolabeled BN analogues in the molecular diagnosis of neuro-endocrine tumors as well as in the targeted treatment of cancer. Taking the above into consideration, three BN analogues were designed and synthesized as potential molecular diagnostics of tumors. Thus, a series of preclinical studies were conducted in order to find out the best candidate for further development in clinical studies. […]Σκοπός: Η παρούσα διατριβή αναφέρεται στην ανάπτυξη νέων πεπτιδικών αναλόγων μπομπεσίνης (ΒΝ) με απώτερο στόχο την ενδεχόμενη κλινική εφαρμογή τους στο πεδίο της διαγνωστικής ογκολογίας με SPECT (Υπολογιστική Τομογραφία Εκπομπής ενός Φωτονίου, Single-photon emission computed tomography) και PET (Τομογραφία Εκπομπής Ποζιτρονίων, Positron emission tomography). Η ΒΝ αποτελεί έναν εξειδικευμένο πεπτίδιο-προσδέτη για τους υποδοχείς του πεπτιδίου απελευθέρωσης της γαστρίνης (gastrin-releasing peptide receptors, GRPrs), οι οποίοι υπερεκφράζονται στην επιφάνεια διαφόρων τύπων καρκινικών κυττάρων. Οι υποδοχείς GRP δυνητικά θα μπορούσαν να θεωρηθούν ιδανικός στόχος για την απεικόνιση νευροενδοκρινικών όγκων μετά από χορήγηση ραδιοεπισημασμένων παραγώγων ΒΝ, με τεχνικές μοριακής διαγνωστικής, αλλά και για την στοχευμένη θεραπευτική αντιμετώπιση του καρκίνου. Με αυτό τον στόχο σχεδιάστηκαν και συντέθηκαν πεπτιδικά ανάλογα ΒΝ για τα οποία πραγματοποιήθηκε μία σειρά προκλινικών μελετών με σκοπό τη διαμόρφωση και την εφαρμογή ενός πλαισίου διάκρισης των κατάλληλων ραδιοχημικών και ραδιοφαρμακολογικών χαρακτηριστικών τα οποία θα μπορούσαν να οδηγήσουν ένα από αυτά τα υποψήφια διαγνωστικά σκευάσματα του σε κλινικές μελέτες ανίχνευσης του καρκίνου. […

Study of the performance of the ATLAS monitored drift tube chambers under the influence of heavily ionizing α\alpha-particles

The MDT chambers of the ATLAS Muon Spectrometer will operate in a heavy LHC background environment mainly from photons and neutrons. The ionization produced by neutron recoils is much higher than the one from photons or muons and can be simulated by the use of alpha particles. A systematic study of the behavior of the ATLAS Monitored Drift Tubes (MDTs) under controlled irradiation has been performed. The presence of alpha particles results in the reduction of the gas gain due to space charge effects. The gas gain reduction has been studied in a single tube set up using a well controlled radium (/sup 226/Ra) source in order to enrich the tube gas (Ar/CO/sub 2/) with the alpha emitter /sup 220/Rn and irradiate the tubes internally. The results are confronted with Garfield simulations

Radiolabeled PSMA Inhibitors

PSMA has shown to be a promising target for diagnosis and therapy (theranostics) of prostate cancer. We have reviewed developments in the field of radio- and fluorescence-guided surgery and targeted photodynamic therapy as well as multitargeting PSMA inhibitors also addressing albumin, GRPr and integrin &alpha;v&beta;3. An overview of the regulatory status of PSMA-targeting radiopharmaceuticals in the USA and Europe is also provided. Technical and quality aspects of PSMA-targeting radiopharmaceuticals are described and new emerging radiolabeling strategies are discussed. Furthermore, insights are given into the production, application and potential of alternatives beyond the commonly used radionuclides for radiolabeling PSMA inhibitors. An additional refinement of radiopharmaceuticals is required in order to further improve dose-limiting factors, such as nephrotoxicity and salivary gland uptake during endoradiotherapy. The improvement of patient treatment achieved by the advantageous combination of radionuclide therapy with alternative therapies is also a special focus of this review

Radiolabeled PSMA Inhibitors

Simple Summary Prostate cancer remains one of the leading causes of cancer death in men worldwide. Despite the recent success in the development and clinical application of radiopharmaceuticals targeting the prostate-specific membrane antigen (PSMA) for diagnosis and endoradiotherapy of prostate cancer, more research is ongoing to further investigate and improve patient care and quality of life. Herein, an overview of novel developments and applications for small molecule and low-molecular weight radiolabeled PSMA inhibitors with an outlook to clinical translation is given. PSMA has shown to be a promising target for diagnosis and therapy (theranostics) of prostate cancer. We have reviewed developments in the field of radio- and fluorescence-guided surgery and targeted photodynamic therapy as well as multitargeting PSMA inhibitors also addressing albumin, GRPr and integrin alpha(v)beta(3). An overview of the regulatory status of PSMA-targeting radiopharmaceuticals in the USA and Europe is also provided. Technical and quality aspects of PSMA-targeting radiopharmaceuticals are described and new emerging radiolabeling strategies are discussed. Furthermore, insights are given into the production, application and potential of alternatives beyond the commonly used radionuclides for radiolabeling PSMA inhibitors. An additional refinement of radiopharmaceuticals is required in order to further improve dose-limiting factors, such as nephrotoxicity and salivary gland uptake during endoradiotherapy. The improvement of patient treatment achieved by the advantageous combination of radionuclide therapy with alternative therapies is also a special focus of this review