Work Package 6 (WP6): Health

Nuclear Techniques for Health and Radio-Pharmaceuticals

Objectives and intended results

1. Cyclotron Unit:

The worldwide expansion in the number of cyclotron units during the recent years has been driven by the advent of great advances in medical imaging instrumentation (PET, SPECT and, more recently, PET/CT). The scanners are applied clinically for diagnosis of cancer, heart disease, and neurologic disorders, as well as for several other medical studies. The main radioisotope used for PET is ¹⁸F-FDG, since it has gained a widespread clinical acceptance for a variety of applications. Nevertheless, other isotopes have also found important clinical applications as well (¹¹C, ¹³N, ¹⁵O). Moreover, research is directed towards the introduction of new positron emitting radionuclides in medicine, such as ⁶⁴Cu and ¹²⁴I. In addition to medicine, PET has found important industrial applications as well. For example, imaging of ¹¹C enables to study lubricant flow in machine components etc.

Within the CALIBRA infrastructure, an installation that combines a cyclotron unit with automated radioisotope production units for research, medical and industrial applications have been proposed. The final vision of the proposal is the development of a type IV cyclotron installation as described in the Technical Guide “Cyclotron Produced Radiopharmaceuticals: Guidelines for Setting-up a Facility, Technical Report Series No. 471, IAEA, Vienna, 2009”. The facility will have the potential, in addition to its main research activities, to produce radioisotopes for medical applications. The unit will be capable to produce ¹¹C, ¹³N, ¹⁵O, ¹⁸F and, at a later stage after modifications in the target systems, to proceed with the production of ⁶⁴Cu, ⁸⁶Y, ⁸⁹Zr, ¹²³I και ¹²⁴I.

The proposed cyclotron unit in combination with the other operating accelerator units at NCSR-D will provide a unique in Greece research infrastructure enabling scientific research and innovative applications in the areas of radiopharmaceutical research, nuclear chemistry, medical physics, medical informatics and industrial applications of radioisotopes.  The cyclotron unit will meet all the specifications related to radiation protection and the safety of the personnel, the public and the environment from ionizing radiation as described in the National Radiation Protection Regulations and the International Atomic Energy Agency Guides. A group of scientists and technicians will be formed for the transportation, assembling, shielding, installing and commissioning of the cyclotron.

NCSR “Demokritos” is the only research center in Greece that combines the scientific and technological experience in the relevant fields of accelerator technology, radiopharmaceuticals, radioactive waste management, transport of radioactive materials, as well as nuclear security and radiation protection.  Finally, the proposed unit will be the only cyclotron that will be available in research and education in Greece.

1. MicroPIXE:

Targeted delivery of pharmaceuticals and diagnostic products allows an increased therapeutic result with a simultaneous decrease of treatment side effects. This is of great importance, for example, for the delivery of toxic pharmaceuticals used in chemotherapy. In order to achieve successful targeted delivery of the diagnostic or therapeutic products it is of importance to obtain information on the cellular uptake and intracellular distribution of these substances from target tissues or cell populations.

The Pharmaceutical Technology Lab of the University of Patras applies nanotechnology principles and methods for the development of targeted therapies against various types of cancer (breast, bowel, brain). In particular, hybrid, magnetic nanoparticles are being developed in which strong anti-cancer drugs are enclosed for the purpose of selectively dispensing the encapsulated drug into cancerous tumors with an external magnetic field.

In the context of this study, the microPIXE technique will be used to study the uptake and intracellular distribution of nanoparticles and their encapsulated drug (e.g. cisplatin) by analyzing the intracellular distribution of iron and platinum, respectively. The feasibility to use nanoparticles to deliver the pharmaceutical at its site of action, i.e., in the cell nucleus, as well as the concentrations that can be achieved, will be investigated.

1. X-ray Fluorescence Analysis

The human placenta is a temporary tissue formed at the onset of conception. The purpose of the placenta is to facilitate the exchange of elements and other substances between the mother and the fetus. Therefore, inadequate or excessive intake of certain nutritional and toxic elements in pregnancy may affect the development of the fetus.

Scope of the work will be the development of XRF methodology using high-energy and polarized beams for the analysis of trace elements in biological placental samples. The proposed methodology will be generally evaluated for its application to large-scale studies through the collection of relevant data from Greece.

1. Neutron Activation Analysis

Neutron Activation Analysis (NAA) is a nuclear analytical technique with unique capabilities in the analysis of biological samples. The technique requires minimal sample preparation and therefore minimizes lab contamination probability.  NAA is a non-destructive analytical technique and the sample can be re-analyzed if it is required. NAA enables determination of a wide range of element concentrations, ranging from trace elements to major elements. Moreover, enables analysis of sample masses from a fraction of gram to several kilograms. It is accurate and reproducible. Furthermore, the analysis can be performed by absolute or relative calibration techniques, enabling a panoramic analysis of a large number of elements in the sample (i.e., up to 65 elements can be determined by NAA).

Within the CALIBRA project, NAA techniques will be developed for the analysis of biological samples using neutron beams provided by the TANDEM accelerator. The techniques will aim in the study of toxic and essential trace elements in foodstuff and biological tissues. The collaboration will include two NCSR-D institutes (INPP and INRASTES) as well as the University of Ioannina.

Tasks to implement

• Cyclotron Unit

1. Preparation of reports for obtaining the cyclotron transfer license from the Medical Center of Groningen University to NCSR Demokritos
2. Extension of the operation license of the TANDEM lab to include the temporal storage of the cyclotron unit components in its premises
3. Transfer of the cyclotron unit and components from The Netherlands to Greece and safe storage at the TANDEM accelerator lab
4. Preparation of the cyclotron unit feasibility report as well as business plan for its operation
5. Preparation of the Cyclotron Unit Health Physics Report
   • ΜicroPIXE
6. Synthesis and characterization of nanoparticles. The process comprises the production of iron oxide nanoparticles by the technique of reducing iron precursors in the presence of polyacrylic acid-polyethylene glycol copolymers. These particles will trap the active substance through its chemical coupling to the polymeric particle crown
7. Characterization of nanoparticles based on their basic physicochemical characteristics, their colloidal stability and their magnetic properties. Study of their cellular uptake and intracellular distribution in cancer cells
8. Study of cellular uptake of magnetic nanoparticles and drugs from human cancer cell lines in the presence and absence of magnetic fields will be carried out by three methodologies.
   1. I) The first will be based on the determination of the uptake of fluorescent labeled nanoparticles by flow cytometry (FACS),
   2. II) the second will include observation of CLSM uptake and intracellular distribution of nanoparticles

• III) the third will attempt to apply microPIXE technique for determining cellular uptake and intracellular distribution of the nanoparticle and drug.
• X–ray Fluorescence Analysis

1. Development of a methodology for the determination of concentrations of both essential and toxic trace elements in lyophilized placental samples using the XRF technique.
2. Evaluation of results and comparison the sensitivity thresholds achieved with other techniques and analytical methodologies.
   • Neutron Activation Analysis
3. Calculations for the optimization of the design of the neutron irradiation and gamma ray detection systems using state of the art computational codes and cross section data libraries.
4. Experimental characterization of the TANDEM accelerator neutron fields with respect to neutron fluence and energy spectrum. Experimental characterization of the gamma ray detectors efficiencies for the different measurement geometries to be employed.
5. Development of methodology to quantify the results of the analysis.
6. Experiments to validate the methodology and demonstrate the capabilities of developed techniques.

Outputs (Deliverables)