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This work describes the preparation, characterization and functionalization with magnetic nanoparticles of a bone tissue-mimetic scaffold composed of collagen and hydroxyapatite obtained through a biomineralization process. Bone remodeling takes place over several weeks and the possibility to follow it

[EN] Bone is a dynamic tissue that constantly undergoes modeling and remodeling. Bone tissue engineering relying on the development of novel implant scaffolds for the treatment of pre-clinical bone defects has been extensively evaluated by histological techniques. The study of bone remodeling, that takes place over several weeks, is limited by the requirement of a large number of animals and time-consuming and labor-intensive procedures. X-ray-based imaging methods that can non-invasively detect the newly formed bone tissue have therefore been extensively applied in pre-clinical research and in clinical practice. The use of other imaging techniques at a pre-clinical level that act as supportive tools is convenient. This review mainly focuses on nuclear imaging methods (single photon emission computed tomography and positron emission tomography), either alone or used in combination with computed tomography. It addresses their application to small animal models with bone defects, both untreated and filled with substitute materials, to boost the knowledge on bone regenerative processes., The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study is part of a project that has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 645757. This study was co-supported through the Program of Industrial Scholarships of Stavros Niarchos Foundation and through IKY scholarships and co-financed by the European Union (European Social Fund ESF) and Greek national funds through the action entitled Reinforcement of Postdoctoral Researchers, in the framework of the Operational Program Human Resources Development Program, Education and Lifelong Learning of the National Strategic Reference Framework (NSRF) 2014-2020.

Recently, nanoparticles have emerged as promising contrast agents for various imaging applications. In this paper, we present the synthesis and characterization of a novel hybrid nano-structure, consisting of an iron oxide@gold nanoparticle, labeled with technetium-99m, for trimodal SPECT/CT/MRI imaging. The particles showed efficient capabilities as CT/MRI imaging agent and high radiochemical yield, indicating a potential single hybrid material for multimodal SPECT/CT/MRI.

Advances in surfactant-assisted chemical approaches have led the way for the exploitation of nanoscale inorganic particles in medical diagnosis and treatment. In this field, magnetically-driven multimodal nanotools that perform both detection and therapy, well-designed in size, shape and composition, are highly advantageous. Such a theranostic material—which entails the controlled assembly of smaller (maghemite) nanocrystals in a secondary motif that is highly dispersible in aqueous media—is discussed here. These surface functionalized, pomegranate-like ferrimagnetic nanoclusters (40–85 nm) are made of nanocrystal subunits that show a remarkable magnetic resonance imaging contrast efficiency, which is better than that of the superparamagnetic contrast agent Endorem©. Going beyond this attribute and with their demonstrated low cytotoxicity in hand, we examine the critical interaction of such nanoprobes with cells at different physiological environments. The time-dependent in vivo scintigraphic imaging of mice experimental models, combined with a biodistribution study, revealed the accumulation of nanoclusters in the spleen and liver. Moreover, the in vitro proliferation of spleen cells and cytokine production witnessed a size-selective regulation of immune system cells, inferring that smaller clusters induce mainly inflammatory activities, while larger ones induce anti-inflammatory actions. The preliminary findings corroborate that the modular chemistry of magnetic iron oxide nanoclusters stimulates unexplored pathways that could be driven to alter their function in favor of healthcare.

To present a prototype tri-modal imaging system, consisting of a single photon emission computed tomography (SPET), a positron emission tomography (PET), and a computed tomography (CT) subsystem, evaluated in planar mode.The subsystems are mounted on a rotating gantry, so as to be able to allow tomographic imaging in the future. The system, designed and constructed by our group, allows whole body mouse imaging of competent performance and is currently, to the best of our knowledge, unequaled in a national and regional level. The SPET camera is based on two Position Sensitive Photomultiplier Tubes (PSPMT), coupled to a pixilated Sodium Iodide activated with Thallium (NaI(Tl)) scintillator, having an active area of 5x10cmThe scintigraphic mode has a spatial resolution of 1.88mm full width at half maximum (FWHM) and a sensitivity of 107.5cpm/0.037MBq at the collimator surface. The coincidence PET mode has an average spatial resolution of 3.5mm (FWHM) and a peak sensitivity of 29.9cpm/0.037MBq. The X-rays spatial resolution is 3.5lp/mm and the contrast discrimination function value is lower than 2%.A compact tri-modal system was successfully built and evaluated for planar mode operation. The system has an efficient performance, allowing accurate and informative anatomical and functional imaging, as well as semi-quantitative results. Compared to other available systems, it provides a moderate but comparable performance, at a fraction of the cost and complexity. It is fully open, scalable and its main purpose is to support groups on a national and regional level and provide an open technological platform to study different detector components and acquisition strategies.

Polymeric materials are in the epicenter of scientific research the last decade and have been used in a range of pharmaceutical and biological applications. Multifunctional polymeric materials are capable targeting agents, which can be used as controlled drug release vehicles for the enhancement of therapeutic efficacy, as well as for diagnostic purposes. A newer generation of these smart polymeric entities constitutes of smart nanocontainers (NCs), which can navigate the drug to specific areas by avoiding random distribution, and thus resulting in drug toxicity reduction. The combination of pH, thermo and redox sensitivity of the multi stimuli NCs can help to achieve specific release of the drug in the tumor area, where these sensitivity parameters can be observed. Hollow polymeric multi stimuli fluorescent tNCs based on N-(2-Hydroxypropyl)methacrylamide (HPMA) were successfully functionalized with a specific targeting moiety; folic acid, and then characterized morphologically, by scanning electron and transmission electron microscopy, as well as structurally, by Fourier-transform infrared spectroscopy. Their targeting mechanism was investigated in vitro in cervical cancer cell lines and in vivo in tumor bearing mice. According to our results the folic acid functionalized NCs targeted HeLa cells’ surface within the first 30 min of treatment. Human tumor xenografted mice (nonobese diabetic/severe combined immunodeficient) were injected with folate functionalized NCs and their tumor uptake was estimated by γ-imaging at about 3.5%. The targeting efficiency of the folate functionalized NCs was investigated directly in vivo by γ-imaging and indirectly by a tumor efficacy protocol.

Liposomes radiolabelling with diagnostic radionuclides is an excellent tool for studying pharmacokinetics with the view of developing liposome-based drug delivery agents. The aim of the present study is to evaluate the in vitro and in vivo behavior of a 99m Tc-labeled liposome by applying either a direct labeling strategy via a carboxyl group, LP–COOH, or a surface chelating method via pyridyl ethyl cysteine compound (with the intermediate [ 99m Tc (I) (CO) 3 (H 2 O) 3 ] + ), LP-PEC. 99m Tc-LP-COOH was obtained in high radiolabelling yield and radiochemical purity, while 99m Tc (I) (CO) 3 -LP-PEC was initially purified before being in vitro and in vivo evaluated. 99m Tc-LP-COOH was less stable in the presence of competitive for 99m Tc ligands than 99m Tc (I) (CO) 3 -LP-PEC. According to DLS measurements, the presence of serum as well as the applied radiolabelling conditions did not affect the liposomes’ size. The different radiolabelling methods seemed to exert an influence on the biodistribution pattern of the liposomes with the 99m Tc (I) (CO) 3 -LP-PEC showing slow blood clearance, which was also confirmed by in vivo scintigraphic imaging. Nevertheless, passive tumor targeting was attained at a similar extent no matter which radiolabelling technique was followed.

Clustering of biocompatible magnetic iron oxide nanocrystallites (MIONs) is a synthetic strategy which improves magnetic manipulation, imaging, and sensing for biomedical applications. In this work we describe the synthesis of condensed clustered MIONs obtained through biomineralization and epitaxial aggregation in the presence of alginate at ambient conditions, mimicking the process that so far has been achieved only by nature, in iron-oxidizing bacteria. These condensed-type magnetic nanostructures exhibit higher magnetophoretic responses compared to other types of magnetic colloids and clustered systems. The soft environmental conditions used for the synthesis of the magnetic nanosystems enables the alginate coating material to retain high drug loading ability for the doxorubicin molecule as well as strong binding proclivity for radionuclides. The strong binding of doxorubicin forms the physical basis to obtain magnetic nanocarriers, where the selective release of the drug occurs only under the action ...

Introduction Radiolabeled RGD peptides that specifically target integrin α ν β 3 have great potential in early tumor detection through noninvasive monitoring of tumor angiogenesis. Based on previous findings of our group on radiopeptides containing positively charged aminoacids, we developed a new cyclic cRGDfK derivative, c(RGDfK)-(Orn) 3 -CGG. This new peptide availing the polar linker (Orn) 3 and the 99m Tc-chelating moiety CGG (Cys-Gly-Gly) is appropriately designed for 99m Tc-labeling, as well as consequent conjugation onto nanoparticles. Methods A tumor imaging agent, c(RGDfK)-(Orn) 3 -[CGG- 99m Tc], is evaluated with regard to its radiochemical, radiobiological and imaging characteristics. Results The complex c(RGDfK)-(Orn) 3 -[CGG- 99m Tc] was obtained in high radiochemical yield (> 98%) and was stable in vitro and ex vivo . It presented identical to the respective, fully analytically characterized 185/187 Re complex retention time in RP-HPLC. In contrary to other RGD derivatives, we showed that the new radiopeptide exhibits kidney uptake and urine excretion due to the ornithine linker. High tumor uptake (3.87 ± 0.48% ID/g at 60 min p.i.) was observed and was maintained relatively high even at 24 h p.i. (1.83 ± 0.05 % ID/g), thus providing well-defined scintigraphic imaging. Accumulation in other organs was negligible. Blocking experiments indicated target specificity for integrin receptors in U87MG glioblastoma cells. Conclusion Due to its relatively high tumor uptake, renal elimination and negligible abdominal localization, the new 99m Tc-RGD peptide is considered promising in the field of imaging α ν β 3 -positive tumors. However, the preparation of multifunctional SPECT/MRI contrast agents (RGD-conjugated nanoparticles) for dual modality imaging of integrin expressing tumors should be further investigated.

Nanostructured delivery and diagnostic systems that induces specific targeting properties by exploiting the local physicochemical tumour characteristics will be evaluated is the present work. It is well known that cancer cells have specific physicochemical characteristics, which can be taken into consideration for the design of a broad spectrum of drug delivery systems (DDS). Some of those characteristics including the different temperature environment their susceptibility when temperature ranges between 40 and 43 °C where cell apoptosis is induced, the intra- and extra-cellular pH which varies from 6.0 to 6.8, for cancer cells, and 6.5 to 7.4 for normal cells respectively, (lysosomes acidic pH ranges 4–5). Additional significant factors are the overexpressed receptors on the tumour surface. Loading and release studies were carried out by using the anthracycline drug Doxorubicin and their cytotoxicity was evaluated by using the MTT assay in healthy and diseased cell lines. The highlight of this work is the in vitro and in vivo studies which were performed in order to evaluate different nanostructures as for their biodistribution, pharmacokinetic and toxicity per se.

Several preclinical imaging systems are commercially available, but their purchase and maintenance costs make them unaffordable for the majority of small- and medium-sized groups. Taking into account the needs of average users, we developed “γ-eye”, a mouse-sized, benchtop γ-camera suitable for in vivo scintigraphic imaging. The γ-eye is based on two position-sensitive photomultiplier tubes, coupled to a CsI(Na) pixelated scintillator and a low-energy lead collimator with parallel hexagonal holes. The spatial resolution of the system is 2 mm at 0 mm. The energy resolution is 26 % at 140 keV and the maximum recorded sensitivity 210 cps/MBq. The system was evaluated in a proof-of-concept animal study, using three different clinical Tc-99m-labeled radiopharmaceuticals. Phantom and animal studies demonstrate its ability to provide semiquantitative results even for short scans. Systems’ performance, dimensions, and cost make γ-eye a unique solution for efficient whole-body mouse nuclear imaging.

Purpose The main goal of the present study was to investigate the importance of the addition of a positively charged aa in the naturally occurring Bombesin (BN) peptide for its utilization as radiodiagnostic agent, taking into consideration the biodistribution profile, the pharmacokinetic characteristics and the tumor targeting ability. Methods Two BN-derivatives of the general structure [M-chelator]-(spacer)-BN(2–14)-NH 2 , where M: 99m Tc or 185/187 Re, chelator: Gly-Gly-Cys-, spacer: -(arginine) 3 -, M-BN-A ; spacer: -(ornithine) 3 -, M-BN-O ; have been prepared and evaluated as tumor imaging agents. Results The peptides under study presented high radiolabelling efficiency (>98%), significant stability in human plasma (>60% intact radiolabelled peptide after 1 h incubation) and comparable receptor binding affinity with the standard [ 125 I-Tyr 4 ]-BN. Their internalization rates in the prostate cancer PC-3 cells differed, although the amount of internalized peptide was the same. The biodistribution and the dynamic γ-camera imaging studies in normal and PC-3 tumor-bearing SCID mice have shown significant tumor uptake, combined with fast blood clearance, through the urinary pathway. Conclusion The addition of the charged aa spacer in the BN structure was advantageous for biodistribution, pharmacokinetics and tumor targeting ability, because it reduced the upper abdominal radioactivity levels and increased tumor/normal tissue contrast ratios.

The reaction of the C-functionalized cyclam chelating agent 1,4,8,11-tetraazacyclotetradecane-6-carboxylic acid (1) with CuCl2 generated a stable and neutral complex 2, which was characterized by elemental analysis, UV/Vis and IR spectroscopy, electrospray ionization mass spectrometry (ESI-MS), EPR spectroscopy and X-ray crystallography. The secondary amine groups of 1 were protected to generate 3, which was further conjugated with the bombesin (BN) derivative H2N-(Ornithine)3-BN(2–14) by a solid phase peptide synthesis method. After cleavage from the resin and deprotection, the resulting product 5 was obtained and characterized with ESI-MS and NMR spectroscopy, and was subsequently complexed under mild conditions with CuCl2 to generate complex 6 in high yield. Complex 6 was characterized with UV/Vis spectroscopy, ESI-MS and EPR spectroscopy. The stability of complexes 2 and 6 was tested against cysteine, histidine and glutathione, and both complexes were found to be stable. The cyclam BN conjugate 5 and its CuII complex 6 were suitable for targeting the gastrin releasing peptide receptors (GRPrs) that are over expressed on PC-3 cells. Both 5 and 6 showed high binding affinity to GRPrs during in vitro cell assays with human PC-3 prostate cancer cells. The half maximal inhibitory concentration (IC50) values observed for 5 and 6 (0.30 ± 0.03 and 0.33 ± 0.03 nM, respectively) were similar to that of the [Tyr]4-BN peptide (0.45 ± 0.04 nM), which was used as standard.

Aim: Targeted biocompatible nanoplatforms presenting multiple therapeutic functions have great potential for the treatment of cancer. Materials & methods: Multifunctional nanocomposites formed by polymeric nanoparticles (PNPs) containing two cytotoxic agents – the drug alisertib and silver nanoparticles – were synthesized. These PNPs have been conjugated with a chlorotoxin, an active targeting 36-amino acid-long peptide that specifically binds to MMP‑2, a receptor overexpressed by brain cancer cells. Results: The individual and synergistic activity of these two cytotoxic agents against glioblastoma multiforme was tested both in vitro and in vivo. The induced cytotoxicity in a human glioblastoma–astrocytoma epithelial‑like cell line (U87MG) was studied in vitro through a trypan blue exclusion test after 48 and 72 h of exposure. Subsequently, the PNPs’ biodistribution in healthy animals and their effect on tumor reduction in tumor‑bearing mice were studied using PNPs radiolabeled with 99mTc. Conclusion: Tumor reduction was achieved in vivo when using silver/alisertib@PNPs–chlorotoxin., JRC.I.4-Nanobiosciences

Giovanni Baldi,1 Costanza Ravagli,1 Filippo Mazzantini,1 George Loudos,2 Jaume Adan,3 Marc Masa,3 Dimitrios Psimadas,2 Eirini A Fragogeorgi,2 Erica Locatelli,4 Claudia Innocenti,5,6 Claudio Sangregorio,5,7 Mauro Comes Franchini4 1CERICOL, Sovigliana-Vinci, Italy; 2Technological Educational Institute of Athens, Athens, Greece; 3Leitat Technological Center, Barcelona, Spain; 4Department of Industrial Chemistry Toso Montanari, University of Bologna, Bologna, 5Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali (INSTM), 6Dipartimento di ChimicaUSchiff, Università di Firenze, Firenze, 7Centro Nazionale delle Ricerche (ICCOM – CNR), Firenze, Italy Abstract: Polymeric nanoparticles with targeting moieties containing magnetic nanoparticles as theranostic agents have considerable potential for the treatment of cancer. Here we report the chemical synthesis and characterization of a poly(D,L-lactide-co-glycolide)-b-poly(ethylene glycol)-based nanocarrier containing iron oxide nanoparticles and human epithelial growth factor receptor on the outer shell. The nanocarrier was also radiolabeled with99mTc and tested as a theranostic nanomedicine, ie, it was investigated for both its diagnostic ability in vivo and its therapeutic hyperthermic effects in a standard A431human tumor cell line. Following radiolabeling with99mTc, the biodistribution and therapeutic hyperthermic effects of the nanosystem were studied noninvasively in vivo in tumor-bearing mice. A substantial decrease in tumor size correlated with an increase in both nanoparticle concentration and local temperature was achieved, confirming the possibility of using this multifunctional nanosystem as a therapeutic tool for epidermoid carcinoma. Keywords: magnetic nanoparticles, polymeric nanocarriers, skin cancer, hyperthermia, single-photon emission computed tomography, imaging

In this study, a novel way of distinguishing the intrinsic relationship between ανβ3 integrin targeting and detection of tumor growth by using a radiolabeled tracer based on a cyclic Arg-Gly-Asp (RGD) peptide was provided. The potential of the in vivo scintigraphic imaging of the developing vasculature from the early stage of tumor growth was evaluated. Alongside with the scintigraphic images, biodistribution studies were performed at distinct time points to validate this noninvasive imaging approach. The ability to noninvasively assess the tumor growth of ανβ3 integrin-positive glioblastoma tumors provides a method to better understand tumor angiogenesis in vivo and allows for a direct assessment of anti-integrin treatment efficacy.

Hypothesis Conventional chemotherapy drugs such as anthracyclines show no specific activity. They destroy cancer cells but also and the healthy ones, and for that reason exhibit high toxicity. In order to alleviate the toxic effects of chemotherapeutic drugs, the administration dose is being minimized, while their reactivity against tumor cells is lessened. This problem can be overcome or at least reduced by using nanoscale drug delivery systems to target the pathogenic area. The present work deals with the synthesis, characterization and biological evaluation of multi-responsive hollow microspheres coated with Hydroxypropyl Cellulose (HPC)-a biocompatible and thermosensitive polysaccharide-conjugated with folic acid as well promising drug vehicles for targeted cancer therapy. Experiments The synthetic route consists of two steps. In the first step, a single layer of sensitive copolymers is ((Methacrylic acid (MAA), N-(2-Hydroxypropyl) methacrylamide (HPMA) and N,N′-(disulfanediylbis(ethane-2,1-diyl))bis(2-methylacrylamide) (DSBMA)) fabricated on a sacrificial template of SiO 2 and in the second step, an additional layer of the folic acid modified HPC coat the microspheres’ surface. The layers fabrication is performed through a combination of distillation precipitation co-polymerization and chemical deposition method. The loading capacity (% LC) and encapsulation efficiency (% EE) percentages of the chemotherapeutic agent daunorubicin (DNR) in the fabricated microspheres were calculated through the standard curve methodology. In addition, the releasing properties of the resulting spheres are investigated, using the above mentioned methodology. It is worth mentioning that, spheres release the entrapped drug under combined conditions such acidic and reductive environment along with conventional hyperthermia. Cytotoxic activity of the synthesized spheres was investigated by using the well-established method of MTT assay in MCF-7 (breast cancer), HeLa (cervical cancer) and HEK 293 (Human Embryonic Kidney healthy cells) cell lines. Confocal and fluorescence microscopy were used to confirm the in vitro targeted ability of folic acid modified drug loaded microspheres in HeLa, to that overexpress folate receptors, MCF-7 and 3T3 cells, as negative folate cell substrate. Finally, radiolabelling of the spheres is performed, with a gamma emitting radionuclide ( 99m Tc), to assess their in vivo profile by means of scintigraphic imaging and biodistribution studies. Findings Hollow spheres release the encapsulated drug under acidic environment, conventional hyperthermia or in the presence of glutathione (reductive environment). The ability of modified drug carriers to target the HeLa cells, was confirmed by confocal and fluorescence microscopy. The resulting spheres are observed to be promising drug-carriers for cancer treatment due to their releasing properties under tumor’s environment and high concentration in HeLa cells via endocytosis. In addition, the empty vehicles have no toxicity in healthy cells and present antimicrobial activity.

Hypothesis Dual-modality imaging agents, such as radiolabeled iron oxide nanoparticles (IO-NPs), are promising candidates for cancer diagnosis and therapy. We developed and evaluated aminosilane coated Fe 3 O 4 (10 ± 2 nm) as a tumor imaging agent in nuclear medicine through 3-aminopropyltriethoxysilane (APTES) functionalization. We evaluated this multimeric system of targeted 99m Tc-labeled nanoparticles (NPs) conjugated with a new RGD derivate (cRGDfK-Orn 3 -CGG), characterized as NPs-RGD as a potential thermal therapy delivery vehicle. Experiments Transmission Electron Microscopy (TEM) and spectroscopy techniques were used to characterize the IO-NPs indicating their functionalization with peptides. Radiolabeled IO-NPs (targeted, non-targeted) were evaluated with regard to their radiochemical, radiobiological and imaging characteristics. In vivo studies were performed in normal and α ν β 3 -positive tumor (U87MG glioblastoma) bearing mice. We also demonstrated that this system could reach ablative temperatures in vivo . Findings Both radiolabeled IO-NPs were obtained in high radiochemical yield (>98%) and proved stable in vitro . The in vivo studies for both IO-NPs have shown significant liver and spleen uptake at all examined time points in normal and U87MG glioblastoma tumor-bearing mice, due to their colloidal nature. We have confirmed through in vivo biodistribution studies that the non-targeted 99m Tc-NPs poorly internalized in the tumor, while the targeted 99m Tc-NPs-RGD, present 9-fold higher tumor accumulation at 1 h p.i. Accumulation of both IO-NPs in other organs was negligible. Blocking experiments indicated target specificity for integrin receptors in U87MG glioblastoma cells. The preliminary in vivo study of applied alternating magnetic field showed that the induced hyperthermia is feasible due to the aid of IO-NPs.

Έχει αποδειχθεί υπερέκφραση πεπτιδικών υποδοχέων απελευθέρωσης γαστρίνης (GRP-Rs) σε διαφόρους τύπους καρκίνου. Η Μπομπεσίνη, ένα δεκατετραπεπτίδιο ανάλογο των πεπτιδίων απελευθέρωσης γαστρίνης (GRP), έχει απομονωθεί στα θηλαστικά και εμφανίζει υψηλή συγγένεια δέσμευσης και ειδικότητα με τους υποδοχείς απελευθέρωσης γαστρίνης (GRP-Rs). Πρόσφατα, σημαντικό ερευνητικό ενδιαφέρον έχει επιδειχθεί διεθνώς όσον αφορά στο σχεδιασμό αναλόγων Μπομπεσίνης (BN) 8 ή 14 αμινοξικών καταλοίπων επισημασμένων είτε με ραδιοϊσότοπα που εκπέμπουν γ και β+ σωματιδιακή ακτινοβολία είτε με ραδιοϊσότοπα που εκπέμπουν ηλεκτρόνια β- και α σωματιδιακή ακτινοβολία για διάγνωση και θεραπεία αντίστοιχα καρκινικών όγκων. Ο σκοπός της παρούσας μελέτης είναι να εξετάσει εάν η παρεμβολή ή μη ενός βασικού συνδετικού μορίου πεπτιδικής φύσεως μεταξύ του σχηματιζόμενου συμπλόκου του Τεχνητίου και της φαρμακολογικά δραστικής ομάδας του πεπτιδίου Μπομπεσίνης επηρεάζει τη φαρμακοκινητική συμπεριφορά των νέων ενώσεων, για εξειδικευμένη στόχευση καρκίνου του προστάτη. Στα πλαίσια της παραπάνω μελέτης έχουν συντεθεί με την μέθοδο πεπτιδικής σύνθεσης σε στερεά φάση και έχουν μελετηθεί δυο ανάλογα του τύπου: Gly-Gly-Cys-X-BN[2-14] όπου, είτε το συνδετικό μόριο δεν υπάρχει: Χ=0 ΒΝ(Ι), είτε αυτό είναι: X=Orn-Orn-Orn (Orn: α,δ-διαμινοβαλερικό οξύ ή 2,5 διαμινοπεντανοϊκό οξύ ή ορνιθίνη) ΒΝ(ΙΙ). Τα παράγωγα του Τεχνητίου, των δύο νέων πεπτιδικών (ΒΝ) μορίων, 99mTc-BN(Ι) και 99mTc-BN(ΙΙ), ελήφθησαν με ραδιοχημική καθαρότητα >98% και με σχεδόν ίδιους χρόνους έκλουσης από τη στήλη RP-HPLC με αυτούς των αντίστοιχων συμπλόκων του Ρηνίου 185/187Re-BN(Ι) και 185/187Re-BN(ΙΙ) τα οποία χαρακτηρίστηκαν με MS-ESI. Η μεταβολική σταθερότητα βρέθηκε υψηλή στο πλάσμα, μέτρια σε εναιώρημα καρκινικών κυττάρων του προστάτη (PC-3) και σχετικά χαμηλή σε ομογενοποίημα ήπατος και νεφρών. Το παράγωγο 99mTc-BN(I) ήταν λιγότερο σταθερό στο εναιώρημα κυττάρων και στο ομογενοποίημα ήπατος σε σχέση με το 99mTc-ΒΝ(ΙΙ). Ικανοποιητική κρίθηκε η συγγένεια δέσμευσης (της τάξης των nM) με τους GRP-Rs υποδοχείς, και των δύο παραγώγων, καθώς και των συμπλόκων τους με 185/187Re. Το BN(II) εμφανίζει την υψηλότερη συγγένεια. To ποσοστό της εσωτερικοποιημένης ραδιενέργειας στα καρκινικά κύτταρα PC-3 μετά την επώαση τους με το 99mTc-ΒΝ(Ι) ήταν ~6% και με το 99mTc-ΒΝ(ΙΙ) ~25%. Η in vivo αξιολόγηση σε φυσιολογικά πειραματόζωα τύπου Swiss και σε παθολογικά πρότυπα καρκίνου του προστάτη, σε πειραματόζωα τύπου SCID, έδειξε ότι το 99mTc-BN(II) παρουσίασε υψηλότερη συγκέντρωση στο πάγκρεας και στον όγκο σε σχέση με το 99mTc-BN(I). Με τη σπινθηρογραφική δυναμική μελέτη σε παθολογικά πρότυπα καρκίνου του προστάτη μετά τη χορήγηση με 99mTc-ΒΝ(Ι) και 99mTc-BN(II), ελήφθησαν ευκρινείς εικόνες του όγκου, ιδιαίτερα για το 99mTc-BN(II). Εν κατακλείδι, η διεξοδική μελέτη των δύο νέων παραγώγων N3S-X-BN[2-14] έδειξε ότι η υδροφιλικότητα και το φορτίο επηρεάζουν σημαντικά τις in vitro και in vivo ιδιότητες δέσμευσης και την φαρμακοκινητική των παραγώγων της Μπομπεσίνης.

This paper deals with the synthesis, characterization and property evaluation of drug-loaded magnetic microspheres with pH-responsive cross-linked polymer shell. The synthetic procedure consists of 3 steps, of which the first two comprise the synthesis of a poly methyl methacrylate (PMMA) template and the synthesis of a shell by using acrylic acid (AA) and methyl methacrylate (MMA) as monomers, and divinyl benzene (DVB) as cross-linker. The third step of the procedure refers to the formation of magnetic nanoparticles on the microsphere's surface. AA that attaches pH-sensitivity in the microspheres and magnetic nanoparticles in the inner and the outer surface of the microspheres, enhance the efficacy of this intelligent drug delivery system (DDS), which constitutes a promising approach toward cancer therapy. A number of experimental techniques were used to characterize the resulting microspheres. In order to investigate the in vitro controlled release behavior of the synthesized microspheres, we studied the Dox release percentage under different pH conditions and under external magnetic field. Hyperthermia caused by an alternating magnetic field (AFM) is used in order to study the doxorubicin (Dox) release behavior from microspheres with pH functionality. The in vivo fate of these hybrid-microspheres was tracked by labeling them with the γ-emitting radioisotope (99m)Tc after being intravenously injected in normal mice. According to our results, microsphere present a pH depending and a magnetic heating, release behavior. As expected, labeled microspheres were mainly found in the mononuclear phagocyte system (MPS). The highlights of the current research are: (i) to illustrate the advantages of controlled release by combining hyperthermia and pH-sensitivity and (ii) to provide noninvasive, in vivo information on the spatiotemporal biodistribution of these microsphere by dynamic γ-imaging.

Menstrual and reproductive factors and exogenous hormone use have been investigated as pancreatic cancer risk factors in case-control and cohort studies, but results have been inconsistent. We conducted a prospective examination of menstrual and reproductive factors, exogenous hormone use and pancreatic cancer risk (based on 304 cases) in 328,610 women from the EPIC cohort. Then, in a case-control study nested within the EPIC cohort, we examined 12 single nucleotide polymorphisms (SNPs) in CYP17A1 (an essential gene in sex steroid metabolism) for association with pancreatic cancer in women and men (324 cases and 353 controls). Of all factors analyzed, only younger age at menarche (

It has been shown that gastrin releasing peptide receptors (GRPRs) are overexpressed in various types of cancer cells. Bombesin is an analogue of the mammalian GRP that binds with high specificity and affinity to GRPRs. Significant research efforts have been lately devoted to the design of radiolabeled 8 or 14 aminoacid bombesin (BN) peptides for the detection (either with gamma or positron emitting radionuclides) and therapy (with beta(-) emitting radionuclides) of cancer. The specific aim of the present study was to further investigate the radiolabeled peptide structure and to determine whether the total absence of a linker or the use of a basic diverse amino acid linker could influence the biodistribution profile of the new compounds for specific targeting of human prostate cancer. Thus, two new derivatives with the structure Gly-Gly-Cys-X-BN[2-14], where linker X is either zero (I) or Orn-Orn-Orn (Orn: ornithine) (II) were designed and synthesized. The corresponding (99m)Tc-BN derivatives were obtained with high radiochemical yield (>98%) and had almost identical retention times in RP-HPLC with the (185/187)Re complexes, which were also characterized by ESI-MS. Metabolic stability was found to be high in human plasma, moderate in PC-3 cells, and rather low in mouse liver and kidney homogenates for both BN derivatives studied. The BN derivative without the spacer was less stable in cell culture and liver homogenates. A satisfactory binding affinity to GRPRs, in the nanomolar range, was obtained for both BN derivatives as well as for their Re complexes, with BN (II) demonstrating the highest one. In vitro internalization/externalization assays indicated that approximately 6% of BN (I) and approximately 25% of BN (II) were internalized into PC-3 cells. In vivo evaluation in normal Swiss mice and in tumor bearing SCID mice showed that BN (II) presented higher tumor and pancreas uptake than BN (I). Small animal SPECT dynamic imaging, carried out after an injection of BN (II) in mice bearing PC-3 tumors, resulted in PC-3 tumor delineation with low background activity. Overall, this study performed for two new N(3)S-X-BN[2-14] derivatives indicated that hydrophilicity and charge strongly affected the in vitro and in vivo binding properties and the biodistribution pattern. This finding is confirmed by SPECT imaging of BN (II), which is under further in vivo evaluation for detecting cancer-positive GRPRs.

In this work we present the design and development of a prototype SPECT/PET/CT system, suitable for whole body small animal imaging, which is unique not only in national but also in regional level. The integrated SPECT/PET/CT system has three components and is mounted on a rotating gantry, which is designed specifically for such applications. The system is unique on national and regional level. The SPECT component has a 2mm spatial resolution, the PET components a 2.5mm spatial resolution and the X-ray component was recently purchased and is now mounted on the existing gantry and will be evaluated. The complete design of the system and evaluation results are presented.

The combination of imaging and therapy has opened the very promising Theranostics domain with magnetic hyperthermia being a very promising domain. However, imaging systems should not interact with the magnetic field. In this work we have tested the recent C-series of SensL SiPM with 3mm pixel size, 4×4 arrays, coupled to different scintillators and irradiated with various gamma energies. The evaluation of the SiPM arrays shows that 1x1mm pixel size can be clearly resolved at PET energies for GAGG:Ce and CsI:Na and 1.5×1.5mm in SPECT imaging for CsI:Na. The best energy resolution was measured equal to 10.5% under 511keV irradiation for the 2×2mm GAGG:Ce; 16% under 511keV irradiation for the 1×1mm GAGG:Ce and 22% under 120keV irradiation for the 1×1mm CsI:Na. In addition, measurements with position sensitive photomultipliers have been carried out, to evaluate the effect of the magnetic field on the imaging performance of the system. While the effect of the magnetic field outside the coil is small, optimal images will be obtained if the imaging system is placed inside the coil, something that can be achieved only by using SiPMs.