Behrooz Khorsandi

Molecular Targeting and Treatment of an Epidermal Growth Factor Receptor–Positive Glioma Using Boronated Cetuximab

Purpose: The purpose of the present study was to evaluate the anti–epidermal growth factor monoclonal antibody (mAb) cetuximab (IMC-C225) as a delivery agent for boron neutron capture therapy (BNCT) of a human epidermal growth factor receptor (EGFR) gene-transfected rat glioma, designated as F98EGFR. Experimental Design: A heavily boronated polyamidoamine dendrimer was chemically linked to cetuximab by means of the heterobifunctional reagents N-succinimidyl 3-(2-pyridyldithio)-propionate and N-(k-maleimido undecanoic acid)-hydrazide. The bioconjugate, designated as BD-C225, was specifically taken up by F98EGFR glioma cells in vitro compared with receptor-negative F98 wild-type cells (41.8 versus 9.1 μg/g). For in vivo biodistribution studies, F98EGFR cells were implanted stereotactically into the brains of Fischer rats, and 14 days later, BD-C225 was given intracerebrally by either convection enhanced delivery (CED) or direct intratumoral (i.t.) injection. Results: The amount of boron retained by F98EGFR gliomas 24 h following CED or i.t. injection was 77.2 and 50.8 μg/g, respectively, with normal brain and blood boron values <0.05 μg/g. Boron neutron capture therapy was carried out at the Massachusetts Institute of Technology Research Reactor 24 h after CED of BD-C225, either alone or in combination with i.v. boronophenylalanine (BPA). The corresponding mean survival times (MST) were 54.5 and 70.9 days (P = 0.017), respectively, with one long-term survivor (more than 180 days). In contrast, the MSTs of irradiated and untreated controls, respectively, were 30.3 and 26.3 days. In a second study, the combination of BD-C225 and BPA plus sodium borocaptate, given by either i.v. or intracarotid injection, was evaluated and the MSTs were equivalent to that obtained with BD-C225 plus i.v. BPA. Conclusions: The survival data obtained with BD-C225 are comparable with those recently reported by us using boronated mAb L8A4 as the delivery agent. This mAb recognizes the mutant receptor, EGFRvIII. Taken together, these data convincingly show the therapeutic efficacy of molecular targeting of EGFR using a boronated mAb either alone or in combination with BPA and provide a platform for the future development of combinations of high and low molecular weight delivery agents for BNCT of brain tumors.

Post Irradiation Evaluation of Thermal Control Coatings and Solid Lubricants to Support Fission Surface Power Systems

The development of a nuclear power system for space missions, such as the Jupiter Icy Moons Orbiter or a lunar outpost, requires substantially more compact reactor design than conventional terrestrial systems. In order to minimize shielding requirements and hence system weight, the radiation tolerance of component materials within the power conversion and heat rejection systems must be defined. Two classes of coatings, thermal control paints and solid lubricants, were identified as material systems for which limited radiation hardness information was available. Screening studies were designed to explore candidate coatings under a predominately fast neutron spectrum. The Ohio State Research Reactor Facility staff performed irradiation in a well characterized, mixed energy spectrum and performed post irradiation analysis of representative coatings for thermal control and solid lubricant applications. Thermal control paints were evaluated for 1 MeV equivalent fluences from 1013 to 1015 n/cm2. No optical degr...

Monte Carlo Modeling of Count Rates and Defects in a Silicon Carbide Detector Neutron Monitor System, Highlighting GT-MHR

Focusing on the gas turbine-modular helium reactor (GT-MHR), we have developed methods to predict the positions in a nuclear reactor where silicon carbide (SiC) semiconductor diode detectors may work functionally as neutron monitors for at least one refueling cycle. Using MCNP and TRIM, we determined the count rate due to fast neutron-induced primary knock-on atoms and tritons, and the number of displacement damage defects that are created per count and over a refueling cycle, for SiC diode detectors placed at four different radial locations in the central reflector of the GT-MHR. We found that although the total count rates for the SiC detectors placed in locations close to the fuel elements were highest (˜1.2 × 106 counts/s), at those locations the detectors cannot tolerate the damage caused by fast neutrons for a reactor refueling cycle. On the contrary, for SiC detectors placed at the center of the central reflector, where the thermal neutron flux is the dominant flux component, the detectors can survive a GT-MHR refueling cycle. At this location, the total count rate for the SiC diode detectors that we have analyzed is ˜1.6 × 105 counts/s.

SiC Based Neutron Flux Monitors for Very High Temperature Nuclear Reactors

The Gas Turbine-Modular Helium Reactor (GT-MHR) and the Very-High-Temperature Reactor (VHTR) are next-generation high-temperature reactor types that are being designed to operate under normal conditions with primary coolant outlet temperatures in the range of 850 °C and 1000 °C, respectively. A new type of silicon carbide based diode neutron detector is currently under development in order to monitor the neutron flux in this environment. An important problem, in this context, is the long-time reliability of the diodes under continuous irradiation at high temperatures. In this paper, we discuss a computational methodology to study the accumulation of radiation damage in the detectors as a function of temperature and its influence on the electrical properties.

TRIM Modeling of Displacement Damage in SiC for Monoenergetic Neutrons

Although silicon carbide is a very good semiconductor material for the fabrication of diode detectors for use as neutron power monitors in nuclear reactors, the electrical properties of the diodes may be altered because of interactions between energetic neutrons and SiC atoms. If the energy that is transferred from a neutron to an atom in a collision exceeds some threshold value, the atom will be moved from its original position, creating displacement damage. Accurately modeling displacement damage is a first step to finding ways to eliminate or decrease the amount of damage the displacements induce. The methodology that we have used to estimate the number of displacements per atom per fluence, using two codes (MCNP and TRIM) is presented in this paper, along with examples of the results of our calculations.

ANALYSIS OF DISPLACEMENT DAMAGE DOSE AND LOW ANNEALING TEMPERATURES ON THE I-V CHARACTERISTICS OF SiC SCHOTTKY DIODES USING ANOVA METHOD

Abstract Silicon carbide (SiC) is a promising semiconductor material for use in solid-state radiation detectors. SiC’s wide bandgap makes it an appropriate semiconductor for high-temperature applications. Because of the annealing process that occurs at temperatures above 150°C for SiC, SiC semiconductors may function in a radiation environment for longer periods of time at elevated temperatures than at room temperature. Unlike thermal annealing effects that can act to improve the electrical characteristics of SiC, fast neutrons create displacement damage defects in SiC Schottky diodes through scattering and thus rapidly degrade the electrical properties of the SiC diodes. We irradiated SiC Schottky diodes at the Ohio State University Research Reactor at room temperature with neutrons for displacement damage doses (Dd’s) ranging from 7.6 × 1010 to 3.8 × 1011 MeV/g. After irradiation, we annealed the diodes, at either 175 or 300°C. We measured the SiC diodes’ forward bias resistances at different steps of the experiments. To perform the experiments and study the results meaningfully, we performed a full factorial design of experiments with two factors: Dd and annealing temperature. The Dd factor had five levels of treatment, and the temperature had three levels of treatment. We did one-way and two-way analysis of variance to understand which factor is more dominant and whether or not the interaction effects are significant. It was determined that for Dd up to 2.3 × 1011 MeV/g the fractional damage recovery decreases with increasing Dd, but that Dd is not a significant factor affecting further changes in damage recovery for Dd’s ranging from 2.3 × 1011 to 3.8 × 1011 MeV/g when the annealing temperature varies between 175 and 300°C. For high Dd (greater than 2.3 × 1011 MeV/g) neutron irradiations, the annealing temperature significantly affects the damage recovery.

Neutron Damage in SiC Semiconductor Radiation Detectors in the GT-MHR

As a part of a U.S. Department of Energy Nuclear Engineering Research Initiative (NERI) project, we are evaluating the potential for using silicon carbide (SiC) semiconductor radiation detectors, operating in the pulse mode, as power monitors for gas turbine modular helium reactor (GT-MHR) [1]. Locations for the power monitors will be selected considering acceptable detector count rates and lifetimes. We have characterized the radiation environment at various locations in the GT-MHR, where detectors may be placed, in terms of the 1 MeV equivalent neutron flux in SiC (φeq,1 MeV, SiCTotal). Also, we have characterized the radiation field in beam part 1 (BP1) of the Ohio State University Research Reactor (OSURR) in these same terms, with the intent of correlating observed degradation of the SiC detectors in the OSURR to the degradation that can be expected for various detector locations in the GT-MHR. Comparing φeq,1 MeV, SiCTotal for the GT-MHR and for the OSURR, we conclude that SiC devices cannot be adequately tested in the characterization vessel in OSURR BP1 for the radiation damage that would be incurred over a refueling cycle for detectors placed in-core. Also, we note that the radiation environment in the OSURR BP1 is harder than the radiation environment in the GT-MHR.