Microdosimetry for boron neutron capture therapy.

Preclinical studies for boron neutron capture therapy (BNCT) using epithermal neutrons are ongoing at several laboratories. The absorbed dose in tumor cells is a function of the thermal neutron flux at depth, the microscopic boron concentration, and the size of the cell. Dosimetry is therefore complicated by the admixture of thermal, epithermal, and fast neutrons, plus gamma rays, and the array of secondary high-linear-energy-transfer particles produced within the patient from neutron interactions. Microdosimetry can be a viable technique for determining absorbed dose and radiation quality. A 2.5-cm-diameter tissue-equivalent gas proportional counter has been built with 50 parts per million (ppm) 10B incorporated into the walls and counting gas to simulate the boron uptake anticipated in tumors. Measurements of lineal energy (y) spectra for BNCT in simulated volumes of 1-10 microns diameter show a dose enhancement factor of 4.3 for 30 ppm boron, and a "y" of 250 keV/microns for the boron capture process. Chamber design plus details of experimental and calculated linear energy spectra will be presented.     

Boronated thymidine analogues for boron neutron capture therapy

Concise synthetic methods for synthesizing 3-carboranyl thymidine analogues (3CTAs) modified with cyclic and acyclic alcohols have been developed. The synthesis of these potential boron neutron capture therapy (BNCT) agents and their preliminary biological evaluation is described.     

Inborn errors of GABA metabolism

Defects in man in four steps of 4-aminobutyric acid (GABA) metabolism may interefere with the function of this major inhibitory neurotransmitter. Glutamic acid decarboxylase, 4-aminobutyric acid aminotransferase, succinic semialdehyde dehydrogenase, and homocarnosinase are closely identified with the brain, but two of these enzymes are expressed in cultured peripheral cells, which may permit novel approaches to the study of the metabolism and regulation of GABA.     

Performance of silicon microdosimetry detectors in boron neutron capture therapy

Reverse-biased silicon p-n junction arrays using Silicon-On-Insulator technology have been proposed as microdosimeters. The performance of such detectors in boron neutron capture therapy (BNCT) is discussed. This work provides the first reported measurements using boron-coated silicon diode arrays as microdosimeters in BNCT. Results are in good agreement with measurements with gas proportional counters. Various boron-coating options are investigated along with device orientation effects. Finally, a 235U coating is tested to simulate the behavior of the device in a heavy-ion therapy beam.     

Inborn errors of purine and pyrimidyne metabolism

Inborn errors of purine and pyrimidine metabolism (P/P) manifest themselves by a variety of clinical picture. They may be recognized at any age and may affect any system--immunological, hematological, neurological, musculoskeletal, and because of the relative insolubility of purine bases, renal as well. At present, a total of 30 defects have been described. Fifteen of them can have serious clinical consequences. Analysis of prevalence estimated by comparing the number of detected P/P patients in Poland and the number of newborns as well as delay of diagnosis, point at insufficient degree of detectability of these defects in our country. It is necessary to improve the education among physicians as well as to popularize screening methods for these defects.     

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. A positive response was defined as a breathing rate 20% above the control group mean and categorized as occurring either early (<110 days) or late (>110 days). The ED(50) values derived from probit analyses of the early breathing rate dose-response data for X rays and neutrons were 11.4+/-0.4 and 9.2+/-0.6 Gy, respectively, and were similar for the other end points. The ED(50) values for irradiation with neutrons plus p-boronophenylalanine were 8.7+/-1.0 and 6.7+/-0.4 for the early and late breathing rate responses, respectively, and 7.0+/-0.5 Gy for the histological response. The RBEs for thermal neutrons ranged between 2.9+/-0.7 and 3.1+/-1.2 for all end points. The weighting factors for the boron component of the dose differed significantly between the early (1.4+/-0.3) and late (2.3+/-0.3) breathing rate end points. A reassessment of doses in patients during cranial BNCT confirmed that the maximum weighted doses were well below the threshold for the onset of pneumonitis in healthy human lung.     

Characterization of neutron beams for boron neutron capture therapy: in-air radiobiological dosimetry

The survival curves and the RBE for the dose components generated in boron neutron capture therapy (BNCT) were determined separately in neutron beams at Japan Research Reactor No. 4. The surviving fractions of V79 Chinese hamster cells with or without 10B were obtained using an epithermal neutron beam (ENB), a mixed thermal-epithermal neutron beam (TNB-1), and a thermal (TNB-2) neutron beam; these beams were used or are planned for use in BNCT clinical trials. The cell killing effect of the neutron beam in the presence or absence of 10B was highly dependent on the neutron beam used and depended on the epithermal and fast-neutron content of the beam. The RBEs of the boron capture reaction for ENB, TNB-1 and TNB-2 were 4.07 +/- 0.22, 2.98 +/- 0.16 and 1.42 +/- 0.07, respectively. The RBEs of the high-LET dose components based on the hydrogen recoils and the nitrogen capture reaction were 2.50 +/- 0.32, 2.34 +/- 0.30 and 2.17 +/- 0.28 for ENB, TNB-1 and TNB-2, respectively. The RBEs of the neutron and photon components were 1.22 +/- 0.16, 1.23 +/- 0.16, and 1.21 +/- 0.16 for ENB, TNB-1 and TNB-2, respectively. The approach to the experimental determination of RBEs outlined in this paper allows the RBE-weighted dose calculation for each dose component of the neutron beams and contributes to an accurate inter-beam comparison of the neutron beams at the different facilities employed in ongoing and planned BNCT clinical trials.     

Towards new boron carriers for boron neutron capture therapy: metallacarboranes and their nucleoside conjugates

Thymidine conjugates containing metallacarborane, {8-[5-(N(3)-thymidine)-3-oxa-pentoxy]-3-cobalt bis(1,2-dicarbollide)}- (5) and {8-[5-(O(4)-thymidine)-3-oxa-pentoxy]-3-cobalt bis(1,2-dicarbollide)}- (6) ions and several simple [3-cobalt bis(1,2-dicarbollide)]- ion (1) derivatives have been studied as potential boron carriers for BNCT. Compound 6 and some nonnucleoside derivatives of 1 were not toxic above 100 microM. The partition coefficient for both metallacarborane bearing thymidine conjugates 5 and 6 was more than 500 times higher than that of unmodified nucleoside. The cellular uptake studies showed accumulation of compounds 6 in V79 Chinese hamster cells but not of compound 5. The low toxicity of conjugate type of 6 together with its high partition coefficient suggest that judicially designed derivatives of metallacarboranes can be considered as potential boron carriers for BNCT.     

New horizons for therapy based on the boron neutron capture reaction

Boron neutron capture therapy (BNCT) is currently undergoing clinical trials in the USA, Japan and The Netherlands with patients afflicted with deadly brain cancer (glioblastoma multiforme) or melanoma. This therapy relies on a binary process in which the capture of a slow neutron by a ¹⁰B nucleus leads to an energetic nuclear fission reaction, with the formation of ⁷Li³⁺ and ⁴He²⁺ and accompanied by about 2.4 MeV of energy. The fleeting ⁷Li³⁺ and ⁴He²⁺ travel a distance of only about the diameter of one cell, and they are deadly to any cell in which they have been produced. Research in progress is concerned with the development of advanced boron agents and neutron sources, other than nuclear reactors, for the treatment of a variety of cancer types using novel ¹⁰B delivery methods. Non-malignant diseases such as rheumatoid arthritis offer additional opportunities for BNCT. The entire BNCT area awaits commercialization.     

Folate receptor-targeted novel boron compound for boron neutron capture therapy on F98 glioma-bearing rats

Radiation and Environmental Biophysics - Folic acid (FA) has high affinity for the folate receptor (FR), which is limited expressed in normal human tissues, but over-expressed in several tumor...     

Transferrin-loaded nido-carborane liposomes: tumor-targeting boron delivery system for neutron capture therapy

The nido-carborane lipid 2 as a double-tailed boron lipid was synthesized from heptadecanol in five steps. The lipid 2 formed stable liposomes at 25% molar ratio toward DSPC with cholesterol. Transferrin was able to be introduced on the surface of boron liposomes (Tf(+)-PEG-CL liposomes) by the coupling of transferrin to the PEG-CO(2)H moieties of Tf(-)-PEG-CL liposomes. The biodistribution of Tf(+)-PEG-CL liposomes, in which (125)I-tyraminyl inulins were encapsulated, showed that Tf(+)-PEG-CL liposomes accumulated in tumor tissues and stayed there for a sufficiently long time to increase tumor/blood concentration ratio, although Tf(-)-PEG-CL liposomes were gradually released from tumor tissues with time. A boron concentration of 22 ppm in tumor tissues was achieved by the injection of Tf(+)-PEG-CL liposomes at 7.2 mg/kg body weight boron in tumor-bearing mice. After neutron irradiation, the average survival rate of mice not treated with Tf(+)-PEG-CL liposomes was 21 days, whereas that of the treated mice was 31 days. Longer survival rates were observed in the mice treated with Tf(+)-PEG-CL liposomes; one of them even survived for 52 days after BNCT.     

Calculation of dose components in head phantom for boron neutron capture therapy.

Application of neutrons to cancer treatment has been a subject of considerable clinical and research interest since the discovery of the neutron by Chadwick in 1932 (3). Boron neutron capture therapy (BNCT) is a technique of radiation oncology which is used in treating brain cancer (glioblastoma multiform) or melanoma and that consists of preferentially loading a compound containing 10B into the tumor location, followed by the irradiation of the patient with a beam of neutron. Dose distribution for BNCT is mainly based on Monte Carlo simulations. In this work, the absorbed dose spatial distribution resultant from an idealized neutron beam incident upon ahead phantom is investigated using the Monte Carlo N-particles code, MCNP 4B. The phantom model used is based on the geometry of a circular cylinder on which sits an elliptical cylinder capped by half an ellipsoid representing the neck and head, both filled with tissue-equivalent material. The neutron flux and the contribution of individual absorbed dose components, as a function of depths and of radial distance from the beam axis (dose profiles) in phantom model, is presented and discussed. For the studied beam the maximum thermal neutron flux is at a depth of 2 cm and the maximum gamma dose at a depth of 4 cm.     

Hyaluronan as carrier of carboranes for tumor targeting in boron neutron capture therapy

Boron neutron capture therapy (BNCT) represents a promising approach for tumor therapy. A critical requirement for BNCT is tumor targeting, a goal that is currently addressed with the development of low and high molecular weight agents capable of interacting with receptors expressed by cancer cells. Here, we describe a new bioconjugate (HApCB) composed by n-propyl carborane linked to hyaluronan (HA) via an ester linkage for a degree of substitution of approximately 30%, leading to a water-soluble derivative. The structure and main physicochemical characteristics of the new HA derivative were determined by means of Fourier transform infrared, fluorescence, and 1H, 13C, and 10B NMR analysis and are herein reported in detail. As HA is recognized by the CD44 antigen, densely populating the surface of many tumor cells, HApCB is expected to deliver boron atoms from the locally released carborane cages directly to target cells for antitumor application in BNCT. In vitro biological experiments showed that HApCB was not toxic for a variety of human tumor cells of different histotypes, specifically interacted with CD44 as the native unconjugated HA, and underwent uptake by tumor cells, leading to accumulation of amounts of boron atoms largely exceeding those required for a successful BNCT approach. Thus, HApCB may be regarded as a promising new BNCT agent for specific targeting of cancer cells overexpressing the CD44 receptor.