Trastuzumab-Modified Gold Nanoparticles Labeled with 211At as a Prospective Tool for Local Treatment of HER2-Positive Breast Cancer.

Highly localized radiotherapy with radionuclides is a commonly used treatment modality for patients with unresectable solid tumors. Herein, we propose a novel α-nanobrachytherapy approach for selective therapy of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This uses local intratumoral injection of 5-nm-diameter gold nanoparticles (AuNPs) labeled with an α-emitter (211At), modified with polyethylene glycol (PEG) chains and attached to HER2-specific monoclonal antibody (trastuzumab). The size, shape, morphology, and zeta potential of the 5 nm synthesized AuNPs were characterized by TEM (Transmission Electron Microscopy) and DLS (Dynamic Light Scattering) techniques. The gold nanoparticle surface was modified by PEG and subsequently used for antibody immobilization. Utilizing the high affinity of gold for heavy halogens, the bioconjugate was labelled with 211At obtained by α irradiation of the bismuth target. The labeling yield of 211At was greater than 99%. 211At bioconjugates were stable in human serum. Additionally, in vitro biological studies indicated that 211At-AuNP-PEG-trastuzumab exhibited higher affinity and cytotoxicity towards the HER2-overexpressing human ovarian SKOV-3 cell line than unmodified nanoparticles. Confocal and dark field microscopy studies revealed that 211At-AuNP-PEG-trastuzumab was effectively internalized and deposited near the nucleus. These findings show promising potential for the 211At-AuNP-PEG-trastuzumab radiobioconjugate as a perspective therapeutic agent in the treatment of unresectable solid cancers expressing HER2 receptors.

Production of Sc medical radioisotopes with proton and deuteron beams.

Proton and deuteron beams (15.3 and 6.8 MeV, respectively) extracted from the PETtrace medical cyclotron at the Radiopharmaceuticals Production and Research Centre in the University of Warsaw, Heavy Ion Laboratory, 28 MeV protons from the C30 cyclotron at the National Centre for Nuclear Research, Swierk, near Warsaw and 33 MeV protons from the ARRONAX accelerator, Nantes were used to produce and investigate the medically interesting Sc radioisotopes. Both natural and isotopically enriched CaCO3 and TiO2 targets were used (42Ca, 43Ca, 44Ca, 48Ca, 48Ti). The production efficiency and isotopic purity were determined and are reported here for the highest commercially available enrichments of the target material. The Thick Target Yield, Activities at the End of Bombardment (EOB) and the relative activities of produced impurities at EOB are reported for 43Sc, 44gSc, 44mSc and 47Sc produced with particle energies below 33 MeV.

211At labeled substance P (5-11) as potential radiopharmaceutical for glioma treatment.

INTRODUCTION: The purposes of the present work were to label substance P (5-11) with 211At using a rhodium(III) complex with a bifunctional ligand-2-(1,5,9,13-tetrathiacyclohexadecan-3-yloxy)acetic acid ([16aneS4]-COOH) and to assess the in vitro stability and toxicity of the obtained radiobioconjugate. METHODS: Two approaches were evaluated to obtain 131I/211At-Rh[16aneS4]-SP5-11 radiobioconjugates, based on 2-step and 1-step syntheses. In the first method 131I/211At-Rh[16aneS4]-COOH complexes were obtained that required further coupling to a biomolecule. In the second approach, the bioconjugate [16aneS4]-SP5-11 was synthesized and further labeled with 131I and 211At through the utilization of a Rh(III) metal cation bridge. The synthesized compounds were analyzed by HPLC, TLC and paper electrophoresis. RESULTS: The 131I/211At-Rh[16aneS4]-COOH complexes were obtained in high yield and possessed good stability in PBS and CSF. Preliminary studies on coupling of 131I-Rh[16aneS4]-COOH to substance P (5-11) in 2-step synthesis showed that this procedure was too long with respect to 211At half-life, prompting us to improve it by finally using a 1-step synthesis. This strategy not only shortened the labeling time, but also increased final yield of 131I/211At-Rh[16aneS4]-SP5-11 radiobioconjugates. The stability of both compounds in PBS and CSF was high. Toxicity studies with the 211At-Rh[16aneS4]-SP5-11 demonstrated that radiobioconjugate significantly reduced T98G cell viability in a dose dependent manner reaching 20% of survival at the highest radioactivity 1200kBq/mL. CONCLUSIONS: The radiobioconjugate 211At-Rh[16aneS4]-SP5-11 revealed its potential in killing glioma T98G cells during in vitro studies; therefore further animal studies to are required to determine its in vivo stability and treatment potential in normal and xenografted mice.

Production of medical Sc radioisotopes with an alpha particle beam.

The internal α-particle beam of the Warsaw Heavy Ion Cyclotron was used to produce research quantities of the medically interesting Sc radioisotopes from natural Ca and K and isotopically enriched 42Ca targets. The targets were made of metallic calcium, calcium carbonate and potassium chloride. New data on the production yields and impurities generated during the target irradiations are presented for the positron emitters 43Sc, 44gSc and 44mSc. The different paths for the production of the long lived 44mSc/44gSc in vivo generator, proposed by the ARRONAX team, using proton and deuteron beams as well as alpha-particle beams are discussed. Due to the larger angular momentum transfer in the formation of the compound nucleus in the case of the alpha particle induced reactions, the isomeric ratio of 44mSc/44gSc at a bombarding energy of 29MeV is five times larger than previously determined for a deuteron beam and twenty times larger than for proton induced reactions on enriched CaCO3 targets. Therefore, formation of this generator via the alpha-particle route seems a very attractive way to form these isotopes. The experimental data presented here are compared with theoretical predictions made using the EMPIRE evaporation code. Reasonable agreement is generally observed.

Cyclotron production of (43)Sc for PET imaging.

BACKGROUND: Recently, significant interest in (44)Sc as a tracer for positron emission tomography (PET) imaging has been observed. Unfortunately, the co-emission by (44)Sc of high-energy γ rays (E γ = 1157, 1499 keV) causes a dangerous increase of the radiation dose to the patients and clinical staff. However, it is possible to produce another radionuclide of scandium-(43)Sc-having properties similar to (44)Sc but is characterized by much lower energy of the concurrent gamma emissions. This work presents the production route of (43)Sc by α irradiation of natural calcium, its separation and purification processes, and the labeling of [DOTA,Tyr3] octreotate (DOTATATE) bioconjugate. METHODS: Natural CaCO3 and enriched [(40)Ca]CaCO3 were irradiated with alpha particles for 1 h in an energy range of 14.8-30 MeV at a beam current of 0.5 or 0.25 µA. In order to find the optimum method for the separation of (43)Sc from irradiated calcium targets, three processes previously developed for (44)Sc were tested. Radiolabeling experiments were performed with DOTATATE radiobioconjugate, and the stability of the obtained (43)Sc-DOTATATE was tested in human serum. RESULTS: Studies of (nat)CaCO3 target irradiation by alpha particles show that the optimum alpha particle energies are in the range of 24-27 MeV, giving 102 MBq/µA/h of (43)Sc radioactivity which creates the opportunity to produce several GBq of (43)Sc. The separation experiments performed indicate that, as with (44)Sc, due to the simplicity of the operations and because of the chemical purity of the (43)Sc obtained, the best separation process is when UTEVA resin is used. The DOTATATE conjugate was labeled by the obtained (43)Sc with a yield >98 % at elevated temperature. CONCLUSIONS: Tens of GBq activities of (43)Sc of high radionuclidic purity can be obtainable for clinical applications by irradiation of natural calcium with an alpha beam.