Depth dose evaluation for prostate cancer treatment using boron neutron capture therapy

Considering the advantages of boron neutron capture therapy (BNCT) in treating prostate cancer, the amount of dose delivered to tumour and healthy tissues must be determined. Therefore, in this study, Monte Carlo analyses were performed to evaluate physical doses of adjacent healthy tissues and prostate tumours located at different depths of reference phantom developed by International Commission on Radiological Protection. According to the results, when prostate depth decreases, the amount of physical dose in tumour increases but the physical doses of healthy organs around the tumour remain constant. As expected, lithium filter decreases the damages to normal tissues. The estimations of physical dose, dose uniformity and dose distribution suggested that using BNCT with a filtered neutron beam could be applicable for prostates locate at the depths less than 7 cm from the body surface, which occurs in 5 % of all subjects.     

Developments in accelerator based boron neutron capture therapy

This paper will review the current status of Boron Neutron Capture Therapy (BNCT), from basic physical mechanisms and clinical indications, to neutron beam development and dosimetry. For in-hospital facilities, particle accelerators presently provide the favoured option, and this paper concentrates on this approach to neutron beam production for BNCT. Various accelerator-based approaches will be reviewed, but discussion will concentrate on the Birmingham programme, particularly the design of a suitable neutron beam delivery system and the experimental validation of Monte Carlo simulations on a mock-up neutron beam moderation system. The use of dose modifying factors to evaluate the likely clinical utility of an epithermal neutron beam will also be discussed, with illustrations from the Birmingham programme.     

Novel carboranyl C-glycosides for the treatment of cancer by boron neutron capture therapy

The synthesis of the novel unprotected carboranyl C-glycosides 2 and 20-24 starting from ethynyl C-glycosides 1, 5-8, 10, and 13 is described. The new compounds are highly water-soluble and display only a very low cytotoxicity, which makes them promising candidates for use in boron neutron capture therapy for the treatment of cancer.     

Liposomes loaded with lipophilic derivative of closo-carborane as a potential boron delivery system for boron neutron capture therapy of tumors

Liposomes encapsulated with lipophilic derivative of 1,2-dicarba-closo-dodecaborane have been obtained and tested for toxicity to glioblastoma U87 cells and biodistribution on a U87MG xenograft mouse model. The liposomes are able to penetrate the tumor and provide boron concentration up to 1.5 mmmmg g–1 with tumor-to-muscle ratio up to 2.4.     

Methods for boron analysis in boron neutron capture therapy (BNCT). A review

The possibilities and limitations of the numerous individual methods used for boron analysis for BNCT in clinical and biological samples are reported in detail. The main interferences of the analytical methods are described. Sample pretreatment techniques are discussed. The methods reviewed for boron analysis for BNCT concern atomic spectrometry, radioanalytical methods, and imaging techniques. An error analysis of boron determinations in biomaterials is performed and typical boron distribution patterns in small mammalians are discussed. Received: 4 December 1998 / Revised: 21 January 1999 / Accepted: 31 January 1999     

Synthesis of dodecaborate-conjugated cholesterols for efficient boron delivery in neutron capture therapy

Dodecaborate-conjugated cholesterols 3a-c were synthesized for liposomal boron delivery systems in neutron capture therapy. The current synthesis is based on the S-alkylation protocol of the cyanoethyl-protected BSH with alkyl halides. The dodecaborate-conjugated cholesterol 3a liposome, which was prepared from dimyristoylphosphatidylcholine (DMPC), cholesterol, dodecaborate-conjugated cholesterol 3a, and polyethyleneglycol-conjugated distearoylphosphatidylethanolamine (PEG-DSPE) (1:0.5:0.5:0.1), exhibited higher cytotoxicity than BSH at the same boron concentration and IC₅₀ values of the 3a liposome and BSH toward colon 26 cells were estimated as 25 and 78 ppm of boron concentration, respectively.     

Synthesis and vesicle formation of a nido-carborane cluster lipid for boron neutron capture therapy

The nido-carborane lipid, which has a double-tailed moiety, was synthesized from heptadecanol in 5 steps. Analysis in a transmission electron microscope by negative staining with uranyl acetate showed that the lipid formed a stable vesicle in which calcein was encapsulated. The lipid was incorporated into distearoylphosphatidylcholine (DSPC) liposomes at a very high concentration.     

Synthesis and characterization of a novel functionalized azanonaborane cluster for boron neutron capture therapy

The reactivity of an azanonaborane cluster containing free amino groups {H2N(CH2)4H2NB8H11NH(CH2)4NH2} towards ketones and aldehydes is investigated. In a one step reaction, the reductive amination of some ketones and aldehydes (namely acetone, benzaldehyde, 3-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 4-nitrobenzaldehyde, 4-acetoxybenzaldehyde, and 4-acetamidobenzaldehyde) with an azanonaborane cluster in the presence of H3BNH2(CH2)4NH2 gives monoalkylamino derivatives of the azanonaborane cluster {RHN(CH2)4H2NB8H11NH(CH2)4NHR} where (R =(Me)2CH-, C6H5CH2-, 3-OHC6H4CH2-, 4-OHC6H4CH2-, 4-NO2C6H4CH2-, 4-MeOCOC6H4CH2-, or 4-NH2COC6H4CH2-). The functionalized derivatives of the {B8N} cluster can be used in boron neutron capture therapy for tumors (BNCT). Similarly, the reductive amination of 5-(4"-formylphenyl)-10,15,20-triphenylporphyrin with the {B8N} cluster gave a porphyrin bearing azanonaborane cluster, while a porphyrin dimer linked by an azanonaborane moiety was obtained following the same method, starting with a 2:1 molar ratio of porphyrin:{B8N} cluster. 5,10,15,20-Tetraformylphenylporphyrin gave the chance to increase the percentage of boron in the resulting boronated porphyrin, which is considered an important factor for a BNCT delivery agent. With these compounds, the cell toxicity using V79 cells was carried out to determine whether these compounds would have favorable biological properties.     

Design of multivalent galactosyl carborane as a targeting specific agent for potential application to boron neutron capture therapy

A multivalent galactosyl carborane derivative 10 (dendritic glyco-borane, DGB) was synthesized and demonstrated as a potential cell-targeting agent in BNCT with HepG2 cells. DGB 10 improved the delivery of boron to HepG2 cells and neutron irradiation data show DGB 10 with ten-fold improvement at killing the HepG2 cells over BSH.     

Synthesis and characterization of azanonaborane-containing purine derivatives for boron neutron capture therapy

Derivatives of purine, adenine, guanine, and 2,6-diaminopurine linked to the azanonaborane (B₈N cluster) have been prepared, for possible use as powerful agents for boron neutron capture therapy (BNCT). The synthesis was carried out via a ligand exchange reaction. The exo-NH₂R group of the azanonaborane of the type [(RH₂N)B₈H₁₁NHR] can be exchanged by one hetero-nitrogen atom of the pyrimidine ring, and except for guanine, also by an N atom of the imidazole ring. The identity of the products was confirmed by NMR, elemental analysis, IR, and mass spectrometry. No reaction was found to occur with caffeine and theophylline under the same reaction conditions.      

Monitoring of gamma emission and neutron transmission during boron neutron capture treatment delivery

The ability to map boron and hydrogen distributions in the body is paramount to the success of boron neutron capture therapy (BNCT). We investigated treatment-time quantitative mapping of these distributions by detecting (i) 0.48 MeV de-excitation photons from neutron capture by boron-10; (ii) 2.22 MeV photons from neutron capture by hydrogen; and (iii) transmitted neutrons. Monte Carlo simulations reported no detectable difference when ¹⁰B in tumour was varied from 0 to 50 ppm, and when the tumour size was varied from 0.0 to 9.5 cm³.     

Novel carboranylporphyrins for application in boron neutron capture therapy (BNCT) of tumors

Condensation of a new carboranylpyrrole 1 with benzaldehydes leads to β-carboranylporphyrins 2 and 3 in good yields. These new porphyrins of high boron content (32-43%) have potential as boron delivery agents for BNCT. The X-ray structures of one β-carboranylporphyrin, of a carboranylpyrrole, and of a side-product are presented.     

Synthesis and characterisation of functionalized borosilicate nanoparticles for boron neutron capture therapy applications

Boron Neutron Capture Therapy (BNCT) is a promising therapy for the cure of diffuse tumors. The successful clinical application of BNCT requires finding new boron-based compounds suitable for an efficient ¹⁰B delivery to the cancerous tissues. The purpose of this work is to synthesize borosilicate nanoparticles by a sol?Cgel recipe, and to functionalize them with folic acid in order to promote their capture by the tumor cells. Whereas sol?Cgel is a promising technique for the synthesis of nanoparticles, in case of borosilicate systems this approach is affected by significant boron loss during preparation. Here we show that functionalization of borosilicate nanoparticles with folic acid can reduce the boron loss. Moreover, preliminary biocompatibility tests indicate that functionalization strongly changes the reactivity of NPs towards blood cells, so favouring the potential use of these materials for clinical applications.     

Crystallographic report: Synthesis and biological evaluation of novel azanonaboranes as potential agents for boron neutron capture therapy

A number of (hydroxyalkylamine)‐N‐(aminoalkyl)azanonaborane(11) derivatives have been synthesized to provide azanonaboranes with different hydrophilic functional groups for use in the treatment of cancer by boron neutron capture therapy (BNCT). The exo‐diamine group of (aminoalkylamine)‐N‐(aminoalkyl)azanonaborane(11) {H₂N(CH₂)_mH₂NB₈H₁₁NH(CH₂)_mNH₂, where m = 4–6} can be substituted by amino alcohol ligands {HO(CH₂)_nNH₂, where n = 3 and 4} to give azanonaboranes containing free amino and hydroxy groups: (3‐hydroxypropylamine)‐N‐(aminobutyl)azanonaborane(11) {HO(CH₂)₃H₂NB₈H₁₁NH(CH₂)₄NH₂}, 1 ; (4‐hydroxybutylamine)‐N‐ (aminobutyl)azanonaborane(11) {HO(CH₂)₄H₂NB₈H₁₁NH(CH₂)₄NH₂}, 2 ; (3‐hydroxypropylamine)‐N‐ (aminopentyl)azanonaborane(11) {HO(CH₂)₃H₂NB₈H₁₁NH(CH₂)₅NH₂}, 3 ; (4‐hydroxypropylamine)‐N‐(aminopentyl)azanonaborane(11) {HO(CH₂)₄H₂NB₈H₁₁NH(CH₂)₅NH₂}, 4 ; (3‐hydroxypropylamine)‐N‐(aminohexyl)azanonaborane(11) {HO(CH₂)₃H₂NB₈H₁₁NH(CH₂)₆NH₂}, 5 . The in vitro toxicity test using Chinese hamster‐V79 cells showed that compounds 1 – 3 were less toxic (LD₅₀ value of ～2.3, 1.7 and 1.4 mM , respectively) than spermine and spermidine (LD₅₀ value of ～0.88 and 0.66 mM , respectively). In vivo distribution experiments of these compounds in Lewis lung carcinoma and B16 melanoma tumor‐bearing mice showed that boron can be found in tumor tissue. The compounds prepared can be considered as a new class of boron containing polyamine compounds that may be useful for boron neutron capture therapy of tumors. Copyright © 2005 John Wiley & Sons, Ltd.     

Closomers of high boron content: synthesis, characterization, and potential application as unimolecular nanoparticle delivery vehicles for boron neutron capture therapy

Unique nanosized closomers of high boron content that may exhibit potential as boron neutron capture therapy target species have been synthesized. The design of these boron-rich nanospheres is based in part on previous work involving dodeca(carboranyl)-substituted closomers [Thomas, J.; Hawthorne, M. F. Chem. Commun. 2001, 1884-1885]. Coupling of ortho-carborane moieties through ester and ether linkages to the rigid [closo-B(12)(OH)(12)](2-) scaffold resulted in the development of a 12(12)-closomer-ester derivative, dodeca[6-(1,2-dicarba-closo-dodecaboran-1-yl)hexanoate]-closo-dodecaborate (2-), 6, and 12(12)-closomer-ether derivatives, dodeca[6-(2-methy1-1,2-dicarba-nido-dodecaboran-1-yl)hexyl]-closo-dodecaborane (14-), 14, and dodeca[6-(7,8-dicarba-nido-dodecaboran-7-yl)hexyl]-closo-dodecaborane (14-), 15. These closomers were investigated by UV-visible spectroscopy and cyclic voltammetry. Additionally, a deboronation method employing NaCN as the nucleophilic reagent was utilized to obtain sodium salts of the ether-linked nido-closomer polyanions, which were purified using a newly developed size-exclusion high pressure liquid chromatography method.     

Synthesis of boron cluster lipids: closo-dodecaborate as an alternative hydrophilic function of boronated liposomes for neutron capture therapy

We succeeded in the synthesis of the double-tailed boron cluster lipids 4a-c and 5a-c, which have a B12H11S moiety as a hydrophilic function, by S-alkylation of B12H11SH (BSH) with bromoacetyl and chloroacetocarbamate derivatives of diacylglycerols for a liposomal boron delivery system on neutron capture therapy. Calcein encapsulation experiments revealed that the liposomes, prepared from the boron cluster lipid 4b, DMPC, PEG-DSPE, and cholesterol, are stable at 37 degrees C in FBS solution for 24 h. [reaction: see text].     

Synthesis of a porphyrin-labelled carboranyl phosphate diester: a potential new drug for boron neutron capture therapy of cancer

A boron-rich, water-soluble porphyrin conjugate was synthesized by coupling of two carboranyl alcohols with 2-chlorophenoxyphosphorus dichloride, followed by conjugation to an amine-functionalized tetraphenyl-porphyrin via an amide linkage.     

10B quantitative determination in ppb range by particle tracks reading for boron neutron capture therapy

Quantitative determination of ppb-order ¹⁰B was carried out in a small number of cultured tumor cells by particle tracks by the ₁₀B(n,)⁷Li reactions using solid state nuclear track detector (SSNTD) for boron neutron capture therapy research. The detection limit of ¹⁰B concentration in tumor cells is less than 1·10^-3 ppm under our experimental conditions which permits the quantitative determination of ¹⁰B in a small number of boronated tumor cells (10⁵/ml = ca. 0.1 mg). Boron quantities in tumor cells determined were well compatible with the tumor cell killing effects of boron neutron capture therapy.