Carborane-containing metalloporphyrins for BNCT

For BNCT of malignant brain tumors, it is crucial that there be relatively high boron concentrations in tumor compared with normal tissues within the neutron-irradiated treatment volume. Fairchild and Bond estimated that major advances in BNCT should be possible if ratios of {sup 10}B concentrations in tumor to those in normal tissue (e.g. brain and blood) were at least 5: 1. Given that the only current boron carrier being tested clinically in the U.S., p-boronophenyl-alanine[BPA], yields tumor blood and tumor brain ratios of about 3:1, the criteria for new boronated compounds should be to at least match these ratios and maintain tumor boron concentrations greater than 30 {mu}g B/g. Although previously tested boronated porphyrins have not only matched but surpassed these ratios, it was at a cost of greater toxicity. Chemical and hematological assays of blood analytes; showed marked thrombocytopenia, a decrease to about one-tenth the normal concentration of platelets circulating in the blood, in addition to abnormalities in concentrations of circulating enzymes, that indicated liver toxicity. The physical appearance and behavior of the affected mice were different from those of mice injected with solvent only. Although thrombocytopenia and other toxic effects had disappeared after a few days, previously tested porphyrins would not be safe to infuse into patients for BNCT of potentially hemorrhagic malignant tumors in the brain such as glioblastoma multiforme and metastatic melanoma. We synthesized a different boronated porphyrin, tetracarboranylphenylporphyrin, [TCP] and inserted nickel, copper, or manganese into its coordination center. Biological studies of NiTCP in mice and of CuTCP in rats show that these compounds elicit little or no toxicity when given at potentially therapeutic doses

BPA uptake in rat tissues after partial hepatectomy

In boron neutron capture therapy (BNCT), boron given as boronophenylalanine (BPA) accumulates transiently not only in tumors but also in normal tissues. Average boron concentrations in transplanted 9L gliosarcoma tumors of 20 rats were 2.5 to 3.7 times concentrations found in blood. Although boron levels in a variety of tissues were also higher than blood the concentrations were less than the lowest found in the tumor. Further note than although BPA is a structural analogue of phenylalanine (Phe), the pathway of BPA uptake into regenerating liver may not be linked to Phe uptake mechanisms

The therapeutic ratio in BNCT: Assessment using the Rat 9L gliosarcoma brain tumor and spinal cord models

During any radiation therapy, the therapeutic tumor dose is limited by the tolerance of the surrounding normal tissue within the treatment volume. The short ranges of the products of the {sup 10}B(n,{alpha}){sup 7}Li reaction produced during boron neutron capture therapy (BNCT) present an opportunity to increase the therapeutic ratio (tumor dose/normal tissue dose) to levels unprecedented in photon radiotherapy. The mixed radiation field produced during BNCT comprises radiations with different linear energy transfer (LET) and different relative biological effectiveness (RBE). The short ranges of the two high-LET products of the `B(n,a)`Li reaction make the microdistribution of the boron relative to target cell nuclei of particular importance. Due to the tissue specific distribution of different boron compounds, the term RBE is inappropriate in defining the biological effectiveness of the {sup 10}B(n,{alpha}){sup 7}Li reaction. To distinguish these differences from true RBEs we have used the term {open_quotes}compound biological effectiveness{close_quotes} (CBE) factor. The latter can be defined as the product of the true, geometry-independent, RBE for these particles times a {open_quotes}boron localization factor{close_quotes}, which will most likely be different for each particular boron compound. To express the total BNCT dose in a common unit, and to compare BNCT doses with the effects of conventional photon irradiation, multiplicative factors (RBEs and CBEs) are applied to the physical absorbed radiation doses from each high-LET component. The total effective BNCT dose is then expressed as the sum of RBE-corrected physical absorbed doses with the unit Gray-equivalent (Gy-Eq)

Might iodomethyl-{alpha}-tyrosine be a surrogate for BPA in BNCT?

A single-photon emission computed tomography [SPECT] imaging agent that is an analogue of a boron carrier for boron neutron-capture therapy [BNCT] of cerebral gliomas would be useful for assessing the kinetics of boron uptake in tumors and in the surrounding brain tissues noninvasively. BNCT is based on the interaction of thermalized neutrons with {sup 10}B nuclei in the targeted tumor. For BNCT of brain tumors, it is crucial that {sup 10}B concentrations in radiosensitive regions of the brain be minimal since malignant cells and vital brain tissues are often inter-mingled at the margins of the tumor. Currently, boronophenylalanine [BPA]-mediated BNCT is undergoing preliminary clinical study for postoperative radiotherapy of glioblastorna multiforme at Brookhaven National Laboratory. Investigators in Japan are developing {sup 18}F-fluoroboronophenylaianine [FBPA] as a positron {sup 18}F (T{sub 1/2} = 110 min), which is usually emission tomography [PET] surrogate for BPA. generated at a cyclotron dedicated to PET, is generally a minimally perturbing substitute for the 2-H on the aromatic ring because of its small size and the strong covalent bond it forms with carbon. However, SPECT has potential advantages over PET: (1) SPECT is clinically more widely available at lower cost; (2) most radioisotopes for the synthesis of SPECT agents can be purchased; (3) SPECT is less difficult to implement. It is thought that the quality of images derived from the two techniques would each be sufficiently informative for BNCT treatment planning purposes, provided that the SPECT and PET agents being considered were both pharmacokinetic surrogates for BPA. This study evaluated the use of {sup 123}I alpha methyltyrosine as a surrogate for BPA in BNCT

Major compound-dependent variations of sup 10 B(n. alpha. ) sup 7 Li RBE for the 9L RAT gliosarcoma in vitro and in vivo

Relative biological effectiveness (RBE) values for the high linear-energy-transfer (LET) radiations produced during born neutron capture therapy (BNCT) were determined using the 9L rat gliosarcorna both in vitro and as an intracerebral tumor. In the absence of {sup 10}B, the combined effect of the recoiling protons from the {sup 14}N(n,p){sup 14}C and the {sup 1}H(n,n{prime})p reactions, compared to an iso-effect endpoint produced by 250 kVp x-rays, yielded RBEs for these high-LET protons of 4.4 in vitro and 3.8 in an in vivo/in vitro assay. RBEs for the {sup 10}B(n,{alpha}){sup 7}Li reaction were calculated from cell survival data following reactor irradiation in the presence or in the absence of the either of the amino acid, p-boronophenylalanine (BPA) or the sulfhydryl dodecaborane dimer (BSSB). With BPA, RBE values ranged from 3.5 to 11.4, while under the same set of conditions with BSSB, RBE values ranged from 1.1 to 4.3. In vitro, higher RBEs for the {sup 10}B(n,{alpha}){sup 7}Li reaction using BPA than with BSSB suggest a difference in distribution of {sup 10}B relative to the nucleus