[Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 is a highly efficient radiotherapeutic for glucagon-like peptide-1 receptor-targeted therapy for insulinoma

PURPOSE: Although metabolic changes make diagnosis of insulinoma relatively easy, surgical removal is hampered by difficulties in locating it, and there is no efficient treatment for malignant insulinoma. We have previously shown that the high density of glucagon-like peptide-1 receptors (GLP-1R) in human insulinoma cells provides an attractive target for molecular imaging and internal radiotherapy. In this study, we investigated the therapeutic potential of [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4, an (111)In-labeled agonist of GLP-1, in a transgenic mouse model of human insulinoma. EXPERIMENTAL DESIGN: [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4 was assessed in the Rip1Tag2 mouse model of pancreatic beta-cell carcinogenesis, which exhibits a GLP-1R expression comparable with human insulinoma. Mice were injected with 1.1, 5.6, or 28 MBq of the radiopeptide and sacrificed 7 days after injection. Tumor uptake and response, the mechanism of action of the radiopeptide, and therapy toxicity were investigated. RESULTS: Tumor uptake was >200% injected activity per gram, with a dose deposition of 3 Gy/MBq at 40 pmol [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4. Other GLP-1R-positive organs showed > or =30 times lower dose deposition. A single injection of [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4 resulted in a reduction of the tumor volume by up to 94% in a dose-dependent manner without significant acute organ toxicity. The therapeutic effect was due to increased tumor cell apoptosis and necrosis and decreased proliferation. CONCLUSIONS: The results suggest that [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4 is a promising radiopeptide capable of selectively targeting insulinoma. Furthermore, Auger-emitting radiopharmaceuticals such as (111)In are able to produce a marked therapeutic effect if a high tumor uptake is achieved.

Future prospects for SPECT imaging using the radiolanthanide terbium-155 — production and preclinical evaluation in tumor-bearing mice

We assessed the suitability of the radiolanthanide 155 Tb (t1/2 = 5.32 days, Eγ = 87 keV (32%), 105 keV (25%)) in combination with variable tumor targeted biomolecules using preclinical SPECT imaging. Methods 155Tb was produced at ISOLDE (CERN, Geneva, Switzerland) by high-energy (~ 1.4 GeV) proton irradiation of a tantalum target followed by ionization and on-line mass separation. 155 Tb was separated from isobar and pseudo-isobar impurities by cation exchange chromatography. Four tumor targeting molecules – a somatostatin analog (DOTATATE), a minigastrin analog (MD), a folate derivative (cm09) and an anti-L1-CAM antibody (chCE7) – were radiolabeled with 155 Tb. Imaging studies were performed in nude mice bearing AR42J, cholecystokinin-2 receptor expressing A431, KB, IGROV-1 and SKOV-3ip tumor xenografts using a dedicated small-animal SPECT/CT scanner. Results The total yield of the two-step separation process of 155 Tb was 86%. 155 Tb was obtained in a physiological l-lactate solution suitable for direct labeling processes. The 155 Tb-labeled tumor targeted biomolecules were obtained at a reasonable specific activity and high purity (> 95%). 155 Tb gave high quality, high resolution tomographic images. SPECT/CT experiments allowed excellent visualization of AR42J and CCK-2 receptor-expressing A431 tumors xenografts in mice after injection of 155 Tb-DOTATATE and 155 Tb-MD, respectively. The relatively long physical half-life of 155 Tb matched in particular the biological half-lives of 155 Tb-cm09 and 155 Tb-DTPA-chCE7 allowing SPECT imaging of KB tumors, IGROV-1 and SKOV-3ip tumors even several days after administration. Conclusions The radiolanthanide 155 Tb may be of particular interest for low-dose SPECT prior to therapy with a therapeutic match such as the β--emitting radiolanthanides 177Lu, 161 Tb, 166Ho, and the pseudo-radiolanthanide 90Y.

Jabetza intelektualaren aurkako delituak interneten. Obren komunikazio publikoa eta P2P saren problematika.

Egunerokotasunean aurrera eramaten ditugun jarduerek mundu juridikoan erreflexua dute modu oso anitzean. Azken hamarkadan jabetza intelektualaren aurkako delituen inguruan eztabaida sakona sortu da, hain zuzen aurrerapen teknologikoek, eta bereziki Interneten globalizazioak ondasun juridiko honen babesean tentsioak sortu dituelako. Teknologia berriek, eta Interneten masifikazioak aukera berriak ireki ditu autoreek beren obrak garatzeko eta publiko handiagoa lortzeko, baina autore edo eskubideen titularrentzat aukera bat dena gehiegikeriaz obrak esplotatzeko bide ere bihurtu da. Honela, Internetek kultura kontsumitzeko modu ezberdin eta berehalakoa sortu du, gure kontsumo ohiturak aldatuz eta eskaintza kultural handiago bat sortuz. Dena den honek gatazka argi bat sortu du kontsumitzaile hauen eta jabetza intelektualaren eskubideen titularren artean, kontsumo kulturala normalean titularren eskubideak errespetatu gabe egiten baita. Tentsio honek bere isla eduki du mundu juridikoan, honen azterketa egingo delarik lan honetan.

Instalazio elektriko adimentsu baten proiektua, autokontsumorako sorkuntza elektrikoarekin, industriako nabe batentzat

Proiektuaren helburua Irulezo enpresaren instalazio elektrikoa eraberritzea da. Egungo behe tentsioko koadro nagusia “smart panel” batetan bilakatuko da, bere kokapena beheko pisuko biltegitik jangelara pasaraziz. Horrela, jangelan behe tentsioko koadro berri bat sortuko da, gaur egun dagoen bigarren mailako koadroa integratuz eta ordezkatuz.