Evaluation of TK1 targeting carboranyl thymidine analogs as potential delivery agents for neutron capture therapy of brain tumors.

In this report we describe studies with N5-2OH, a carboranyl thymidine analog (CTA), which is a substrate for thymidine kinase 1 (TK1), using the F98 rat glioma model. In vivo BNCT studies have demonstrated that intracerebral (i.c.

Energy- and time-resolved detection of prompt gamma-rays for proton range verification.

In this work, we present experimental results of a novel prompt gamma-ray detector for proton beam range verification. The detection system features an actively shielded cerium-doped lanthanum(III) bromide scintillator, coupled to a digital data acquisition system. The acquisition was synchronized to the cyclotron radio frequency to separate the prompt gamma-ray signals from the later-arriving neutron-induced background.

Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer.

Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high grade gliomas, recurrent cancers of the head and neck region and either primary or metastatic melanoma. Neutron sources for BNCT currently have been limited to specially modified nuclear reactors, which are or until the recent Japanese natural disaster, were available in Japan, United States, Finland and several other European countries, Argentina and Taiwan.

Comparison of intracerebral delivery of carboplatin and photon irradiation with an optimized regimen for boron neutron capture therapy of the F98 rat glioma.

In this report we have summarized our studies to optimize the delivery of boronophenylalanine (BPA) and sodium borocaptate (BSH) for boron neutron capture therapy (BNCT) of F98 glioma bearing rats. These results have been compared to a chemoradiotherapeutic approach using the same tumor model. The best survival data from our BNCT studies were obtained using a combination of BPA and sodium borocaptate BSH administered via the internal carotid artery, in combination with blood-brain barrier disruption (BBB-D).

Convection enhanced delivery of carboranylporphyrins for neutron capture therapy of brain tumors.

Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive 10B is irradiated with low energy thermal neutrons to produce α-particles (10B[n,α] Li). Carboranylporphyrins are a class of substituted porphyrins containing multiple carborane clusters. Three of these compounds, designated H2TBP, H2TCP, and H2DCP, have been evaluated in the present study.

Convection enhanced delivery of boronated EGF as a molecular targeting agent for neutron capture therapy of brain tumors.

In the present study, we have evaluated a boronated dendrimer-epidermal growth factor (BD-EGF) bioconjugate as a molecular targeting agent for boron neutron capture therapy (BNCT) of the human EGFR gene-transfected F98 rat glioma, designated F98(EGFR). EGF was chemically linked to a heavily boronated polyamidoamine dendrimer (BD) by means of the heterobifunctional reagent, mMBS. Biodistribution studies were carried out at 6 h and 24 h following intratumoral (i.

Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors.

The purpose of the present study was to evaluate the effectiveness of a 3-carboranyl thymidine analogue (3CTA), 3-[5-{2-(2,3-dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl] thymidine, designated N5-2OH, for boron neutron capture therapy (BNCT) of brain tumors using the RG2 rat glioma model. Target validation was established using the thymidine kinase (TK) 1(+) wild-type, murine L929 cell line and its TK1(-) mutant counterpart, which were implanted s.c.

Functional and histological changes in rat lung after boron neutron capture therapy.

The motivation for this work was an unexpected occurrence of lung side effects in two human subjects undergoing cranial boron neutron capture therapy (BNCT). The objectives were to determine experimentally the biological weighting factors in rat lung for the high-LET dose components for a retrospective assessment of the dose to human lung during cranial BNCT. Lung damage after whole-thorax irradiation was assessed by serial measurement of breathing rate and evaluation of terminal lung histology.

Molecular targeting and treatment of composite EGFR and EGFRvIII-positive gliomas using boronated monoclonal antibodies.

Purpose: The purpose of the present study was to evaluate the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), cetuximab, (IMC-C225) and the anti-EGFRvIII mAb, L8A4, used in combination as delivery agents for boron neutron capture therapy (BNCT) of a rat glioma composed of a mixture of cells expressing either wild-type (F98(EGFR)) or mutant receptors(F98(npEGFRvIII)).

Experimental Design: A heavily boronated polyamidoamine dendrimer (BD) was linked by heterobifunctional reagents to produce the boronated mAbs, BD-C225 and BD-L8A4. For in vivo biodistribution and therapy studies, a mixture of tumor cells were implanted intracerebrally into Fischer rats.

No significant endothelial apoptosis in the radiation-induced gastrointestinal syndrome.

Purpose: This report addresses the incidence of vascular endothelial cell apoptosis in the mouse small intestine in relation to the radiation-induced gastrointestinal (GI) syndrome.

Methods And Materials: Nonanesthetized mice received whole-body irradiation at doses above and below the threshold for death from the GI syndrome with 250 kVp X-rays, (137)Cs gamma rays, epithermal neutrons alone, or a unique approach for selective vascular irradiation using epithermal neutrons in combination with boronated liposomes that are restricted to the blood. Both terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining for apoptosis and dual-fluorescence staining for apoptosis and endothelial cells were carried out in jejunal cross-sections at 4 h postirradiation.

Improved dose targeting for a clinical epithermal neutron capture beam using optional (6)Li filtration.

Purpose: The aim of this study was to construct a (6)Li filter and to improve penetration of thermal neutrons produced by the fission converter-based epithermal neutron beam (FCB) for brain irradiation during boron neutron capture therapy (BNCT).

Methods And Materials: Design of the (6)Li filter was evaluated using Monte Carlo simulations of the existing beam line and radiation transport through an ellipsoidal water phantom. Changes in beam performance were determined using three figures of merit: (1) advantage depth (AD), the depth at which the total biologically weighted dose to tumor equals the maximum weighted dose to normal tissue; (2) advantage ratio (AR), the ratio of the integral tumor dose to that of normal tissue averaged from the surface to the AD; and (3) advantage depth dose rate (ADDR), the therapeutic dose rate at the AD.

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 F98(EGFR).

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 F98(EGFR) glioma cells in vitro compared with receptor-negative F98 wild-type cells (41.

Molecular targeting and treatment of EGFRvIII-positive gliomas using boronated monoclonal antibody L8A4.

Purpose: The purpose of the present study was to evaluate a boronated EGFRvIII-specific monoclonal antibody, L8A4, for boron neutron capture therapy (BNCT) of the receptor-positive rat glioma, F98(npEGFRvIII).

Experimental Design: A heavily boronated polyamido amine (PAMAM) dendrimer (BD) was chemically linked to L8A4 by two heterobifunctional reagents, N-succinimidyl 3-(2-pyridyldithio)propionate and N-(k-maleimidoundecanoic acid)hydrazide. For in vivo studies, F98 wild-type receptor-negative or EGFRvIII human gene-transfected receptor-positive F98(npEGFRvIII) glioma cells were implanted i.

Selective irradiation of the vascular endothelium has no effect on the survival of murine intestinal crypt stem cells.

The possible role of vascular endothelial cell damage in the loss of intestinal crypt stem cells and the subsequent development of the gastrointestinal (GI) syndrome is addressed. Mice received whole-body epithermal neutron irradiation at a dose rate of 0.57 +/- 0.

The MIT user center for neutron capture therapy research.

Neutron capture therapy (NCT) research encompasses a wide range of preclinical and clinical studies needed to develop this promising but complex cancer treatment. Many specialized facilities and capabilities including thermal and epithermal neutron irradiation facilities, boron analysis, specialized mixed-field dosimetry, animal care facilities and protocols, cell culture laboratories, and, for human clinical studies, licenses and review board approvals are required for NCT research. Such infrastructure is essential, but much of it is not readily available within the community.

Boronated epidermal growth factor as a delivery agent for neutron capture therapy of EGF receptor positive gliomas.

The purpose of the present study was to further evaluate a boronated dendrimer (BD)-epidermal growth factor bioconjugate (BD-EGF), administered by means of convection enhanced delivery (CED), as a molecular targeting agent for boron neutron capture therapy (BNCT) of the F98(EGFR) glioma. Twenty-four hours following CED of (125)I-labeled BD-EGF 47.4% of the injected dose (ID) was retained in F98(EGFR) gliomas compared to 12.

Neutron capture therapy of epidermal growth factor (+) gliomas using boronated cetuximab (IMC-C225) as a delivery agent.

Cetuximab (IMC-C225) is a monoclonal antibody directed against both the wild-type and mutant vIII isoform of the epidermal growth factor receptor (EGFR). The purpose of the present study was to evaluate the monoclonal antibody (MoAb), cetuximab, as a boron delivery agent for neutron capture therapy (NCT) of brain tumors. Twenty-four hours following intratumoral (i.

Boron neutron capture therapy: cellular targeting of high linear energy transfer radiation.

Boron neutron capture therapy (BNCT) is based on the preferential targeting of tumor cells with (10)B and subsequent activation with thermal neutrons to produce a highly localized radiation. In theory, it is possible to selectively irradiate a tumor and the associated infiltrating tumor cells with large single doses of high-LET radiation while sparing the adjacent normal tissues. The mixture of high- and low-LET dose components created in tissue during neutron irradiation complicates the radiobiology of BNCT.

Microdosimetric intercomparison of BNCT beams at BNL and MIT.

Microdosimetric measurements have been performed at the clinical beam intensities in two epithermal neutron beams, the Brookhaven Medical Research Reactor and the M67 beam at the Massachusetts Institute of Technology Research Reactor, which have been used to treat patients with Boron Neutron Capture Therapy (BNCT). These measurements offer an independent assessment of the dosimetry used at these two facilities, as well as provide information about the radiation quality not obtainable from conventional macrodosimetric techniques. Moreover, they provide a direct measurement of the absorbed dose resulting from the BNC reaction.

A critical examination of the results from the Harvard-MIT NCT program phase I clinical trial of neutron capture therapy for intracranial disease.

A phase I trial was designed to evaluate normal tissue tolerance to neutron capture therapy (NCT); tumor response was also followed as a secondary endpoint. Between July 1996 and May 1999, 24 subjects were entered into a phase I trial evaluating cranial NCT in subjects with primary or metastatic brain tumors. Two subjects were excluded due to a decline in their performance status and 22 subjects were irradiated at the MIT Nuclear Reactor Laboratory.

Fission reactor neutron sources for neutron capture therapy--a critical review.

The status of fission reactor-based neutron beams for neutron capture therapy (NCT) is reviewed critically. Epithermal neutron beams, which are favored for treatment of deep-seated tumors, have been constructed or are under construction at a number of reactors worldwide. Some of the most recently constructed epithermal neutron beams approach the theoretical optimum for beam purity.

Treatment planning and dosimetry for the Harvard-MIT Phase I clinical trial of cranial neutron capture therapy.

Purpose: A Phase I trial of cranial neutron capture therapy (NCT) was conducted at Harvard-MIT. The trial was designed to determine maximum tolerated NCT radiation dose to normal brain.

Methods And Materials: Twenty-two patients with brain tumors were treated by infusion of boronophenylalanine-fructose (BPA-f) followed by exposure to epithermal neutrons.

A physical dosimetry intercomparison for BNCT.

An intercomparison of physical dosimetry methods used at the Massachusetts Institute of Technology (MIT) and Brookhaven National Laboratory was completed to enable retrospective analysis of BNCT trials. Measurements were performed under reference conditions pertinent to clinical irradiations at the epithermal neutron beam facility of the Brookhaven Medical Research Reactor (BMRR) using procedures developed at MIT during similar trials. Thermal neutron flux was determined from gold foil activation experiments and good agreement was found between the depth profiles measured in-phantom by the two groups.