J. Esposito

A novel 10B-enriched carboranyl-containing phthalocyanine as a radio- and photo-sensitising agent for boron neutron capture therapy and photodynamic therapy of tumours: in vitro and in vivo studies

The synthesis of a Zn(ii)-phthalocyanine derivative bearing four 10B-enriched o-carboranyl units (10B-ZnB4Pc) and its natural isotopic abundance analogue (ZnB4Pc) in the peripheral positions of the tetraazaisoindole macrocycle is presented. The photophysical properties of ZnB4Pc, as tested against model biological systems, were found to be similar with those typical of other photodynamically active porphyrin-type photosensitisers, including a singlet oxygen quantum yield of 0.67. The carboranyl-carrying phthalocyanine was efficiently accumulated by B16F1 melanotic melanoma cells in vitro, appeared to be partitioned in at least some subcellular organelles and, upon red light irradiation, induced extensive cell mortality. Moreover, ZnB4Pc, once i.v.-injected to C57BL/6 mice bearing a subcutaneously transplanted pigmented melanoma, photosensitised an important tumour response, provided that the irradiation at 600-700 nm was performed 3 h after the phthalocyanine administration, when appreciable concentrations of ZnB4Pc were still present in the serum. Analogously, irradiation of the 10B-ZnB4Pc-loaded pigmented melanoma with thermal neutrons 24 h after injection led to a 4 day delay in tumour growth as compared with control untreated mice. These results open the possibility to use one chemical compound as both a photosensitising and a radiosensitising agent for the treatment of tumours by the combined application of photodynamic therapy and boron neutron capture therapy.

Spectrum shaping assessment of accelerator-based fusion neutron sources to be used in BNCT treatment

Abstract Monte Carlo modelling of an irradiation facility, for boron neutron capture therapy (BNCT) application, using a set of advanced type, accelerator based, 3 H(d,n) 4 He (D–T) fusion neutron source device is presented. Some general issues concerning the design of a proper irradiation beam shaping assembly, based on very hard energy neutron source spectrum, are reviewed. The facility here proposed, which represents an interesting solution compared to the much more investigated Li or Be based accelerator driven neutron source could fulfil all the medical and safety requirements to be used by an hospital environment.

Spectrum shaping of accelerator-based neutron beams for BNCT

We describe Monte Carlo simulations of three facilities for the production of epithermal neutrons for Boron Neutron Capture Therapy (BNCT) and examine general aspects and problems of designing the spectrum-shaping assemblies to be used with these neutron sources. The first facility is based on an accelerator-driven low-power subcritical reactor, operating as a neutron amplifier. The other two facilities have no amplifier and rely entirely on their primary sources, a D-T fusion reaction device and a conventional 2.5 MeV proton accelerator with a Li target, respectively.

An irradiation facility for Boron Neutron Capture Therapy application based on a radio frequency driven D-T neutron source and a new beam shaping assembly

A line of the Boron Neutron Capture Therapy (BNCT) research program aimed at the treatment of brain tumors, carried on at the Nuclear Departments of Pisa and Genova Universities (DIMNP and DITEC), is being focused on a new, 3H(d,n)4He (D–T), accelerator-based neutron source concept, developed at Lawrence Berkeley National Laboratory (LBNL). Simple and compact accelerator designs, using mixed D+ T+ ion beam with relatively low energy, ∼100 keV, have been developed which, in turn, can generate high neutron yields. New approaches have thus been started to design an epithermal neutron irradiation facility able to selectively slow the 14.1 MeV D–T neutrons down to the epithermal (1 eV–10 KeV) energy range. New neutron spectrum shifter and filtering materials, as well as different facility layout approaches have been tested. Possible beam shaping assembly models have also been designed. The research demonstrates that a D–T neutron source could be successfully implemented to provide a ∼1×109 n/cm2 s epithermal n...

Towards the final BSA modeling for the accelerator-driven BNCT facility at INFN LNL.

Some remarkable advances have been made in the last years on the SPES-BNCT project of the Istituto Nazionale di Fisica Nucleare (INFN) towards the development of the accelerator-driven thermal neutron beam facility at the Legnaro National Laboratories (LNL), aimed at the BNCT experimental treatment of extended skin melanoma. The compact neutron source will be produced via the (9)Be(p,xn) reactions using the 5 MeV, 30 mA beam driven by the RFQ accelerator, whose modules construction has been recently completed, into a thick beryllium target prototype already available. The Beam Shaping Assembly (BSA) final modeling, using both neutron converter and the new, detailed, Be(p,xn) neutron yield spectra at 5 MeV energy recently measured at the CN Van de Graaff accelerator at LNL, is summarized here.

Be target development for the accelerator-based SPES-BNCT facility at INFN Legnaro.

An accelerator-driven thermal neutron source for BNCT, planned to be installed at the INFN Laboratori Nazionali di Legnaro (LNL), is in progress in the framework of the SPES (selective production of exotic species) research program. The most critical element of such a facility is the construction of a reliable neutron converter based on the (9)Be(p,xn) nuclear reaction, working at a high power level (150 kW) and 5 MeV beam energy, due to the SPES driver constraints. Two original, beryllium-based, target concepts have been designed for such a purpose. The present status of the neutron converter, as well as the test results performed so far on prototypes constructed, is reported here.

Influence of the Generator in-Growth Time on the Final Radiochemical Purity and Stability of Radiopharmaceuticals

At Legnaro laboratories of the Italian National Institute for Nuclear Physics (INFN), a feasibility study has started since 2011 related to accelerated-based direct production of by the 100Mo(p,2n) reaction. Both theoretical investigations and some recent preliminary irradiation tests on 100Mo-enriched samples have pointed out that both the / ratio and the specific activity will be basically different in the final accelerator-produced Tc with respect to generator-produced one, which might affect the radiopharmaceutical procedures. The aim of this work was to evaluate the possible impact of different / isomeric ratios on the preparation of different Tc-labeled pharmaceutical kits. A set of measurements with , eluted from a standard 99Mo/ generator, was performed, and results on both radiochemical purity and stability studies (following the standard quality control procedures) are reported for a set of widely used pharmaceuticals (i.e., -Sestamibi, -ECD, -MAG3, -DTPA, -MDP, -HMDP, -nanocolloids, and -DMSA). These pharmaceuticals have been all reconstituted with either the first [O4]− eluate obtained from a 99Mo/ generator (coming from two different companies) or eluates after 24, 36, 48, and 72 hours from last elution. Results show that the radiochemical purity and stability of these radiopharmaceuticals were not affected up to the value of 11.84 for the / ratio.

The excitation functions of (100)Mo(p,x)(99)Mo and (100)Mo(p,2n)(99m)Tc.

Proton-induced nuclear reactions for generation of (99)Mo and (99m)Tc radionuclides were investigated using the stacked-foil activation technique on 99.05% enriched (100)Mo targets at energies up to Ep=21MeV. Excitation functions of the reactions (100)Mo(p,x)(99)Mo and (100)Mo(p,2n)(99m)Tc have been measured.

Tumor-localizing and radiosensitizing properties of meso-tetra(4-nido-carboranylphenyl)porphyrin (H2TCP)

Background and Purpose: Boron Neutron Capture Therapy (BNCT) is a binary cancer treatment that exploits the short range particles released from a nuclear fission reaction involving the non-radioactive 10B nucleus and low-energy neutrons for the destruction of tumor cells. In this perspective, porphyrins and phthalocyanines can represent a vehicle for the transport of significant amounts of boron to the neoplastic lesion. Material and Methods: B16F1 melanotic melanoma subcutaneously transplanted in C57/BL6 mice has been used as an in vivo model. Pharmacokinetic studies were performed by intratumoral and intravenous injection of a meso-substituted porphyrin containing 36 B atoms per molecule (H2TCP) and the distribution of H2TCP in the tumor was assessed by fluorescence microscopy analysis. The tumor-bearing mice were exposed to the radiation field for 20 min at a reactor power of 5 kW. Results: At 0.5 h after intratumoral administration or at 24 h after intravenous injection, the amount of 10B in the tumor was found to be about 60 ppm and about 6 ppm, respectively. In spite of the different amounts of 10B in the tumor at the time of irradiation, a very similar delay in tumor growth (5-6 days) was induced by neutron irradiation in the two groups of injected mice with respect to control mice. Conclusions: Our results demonstrate that a suitable boron-loaded porphyrin displays a significant affinity for subcutaneous tumors, and upon activation by thermal neutrons, can promote an important response even in a fairly aggressive and generally radioresistant tumor such as melanotic melanoma.

188W/188Re Generator System and Its Therapeutic Applications

The 188Re radioisotope represents a useful radioisotope for the preparation of radiopharmaceuticals for therapeutic applications, particularly because of its favorable nuclear properties. The nuclide decay pattern is through the emission of a principle beta particle having 2.12 MeV maximum energy, which is enough to penetrate and destroy abnormal tissues, and principle gamma rays ( keV), which can efficiently be used for imaging and calculations of radiation dose. 188Re may be conveniently produced by 188W/188Re generator systems. The challenges related to the double neutron capture reaction route to provide only modest yield of the parent 188W radionuclide indeed have been one of the major issues about the use of 188Re in nuclear medicine. Since the specific activity of 188W used in the generator is relatively low (<185 GBq/g), the eluted can have a low radioactive concentration, often ineffective for radiopharmaceutical preparation. However, several efficient postelution concentration techniques have been developed, which yield clinically useful solutions. This review summarizes the technologies developed for the preparation of 188W/188Re generators, postelution concentration of the 188Re perrhenate eluate, and a brief discussion of new chemical strategies available for the very high yield preparation of 188Re radiopharmaceuticals.