In vivo evaluation of the effects of combined boron and gadolinium neutron capture therapy in mouse models.

While boron neutron capture therapy (BNCT) depends primarily on the short flight range of the alpha particles emitted by the boron neutron capture reaction, gadolinium neutron capture therapy (GdNCT) mainly relies on gamma rays and Auger electrons released by the gadolinium neutron capture reaction. BNCT and GdNCT can be complementary in tumor therapy. Here, we studied the combined effects of BNCT and GdNCT when boron and gadolinium compounds were co-injected, followed by thermal neutron irradiation, and compared these effects with those of the single therapies. In cytotoxicity studies, some additive effects (32‒43%) were observed when CT26 cells were treated with both boron- and gadolinium-encapsulated PEGylated liposomes (B- and Gd-liposomes) compared to the single treatments. The tumor-suppressive effect was greater when BNCT was followed by GdNCT at an interval of 10 days rather than vice versa. However, tumor suppression with co-injection of B- and Gd-liposomes into tumor-bearing mice followed by neutron beam irradiation was comparable to that observed with Gd-liposome-only treatment but lower than B-liposome-only injection. No additive effect was observed with the combination of BNCT and GdNCT, which could be due to the shielding effect of gadolinium against thermal neutrons because of its overwhelmingly large thermal neutron cross section.

Moving Forward in the Next Decade: Radiation Oncology Sciences for Patient-Centered Cancer Care.

In a time of rapid advances in science and technology, the opportunities for radiation oncology are undergoing transformational change. The linkage between and understanding of the physical dose and induced biological perturbations are opening entirely new areas of application. The ability to define anatomic extent of disease and the elucidation of the biology of metastases has brought a key role for radiation oncology for treating metastatic disease. That radiation can stimulate and suppress subpopulations of the immune response makes radiation a key participant in cancer immunotherapy. Targeted radiopharmaceutical therapy delivers radiation systemically with radionuclides and carrier molecules selected for their physical, chemical, and biochemical properties. Radiation oncology usage of "big data" and machine learning and artificial intelligence adds the opportunity to markedly change the workflow for clinical practice while physically targeting and adapting radiation fields in real time. Future precision targeting requires multidimensional understanding of the imaging, underlying biology, and anatomical relationship among tissues for radiation as spatial and temporal "focused biology." Other means of energy delivery are available as are agents that can be activated by radiation with increasing ability to target treatments. With broad applicability of radiation in cancer treatment, radiation therapy is a necessity for effective cancer care, opening a career path for global health serving the medically underserved in geographically isolated populations as a substantial societal contribution addressing health disparities. Understanding risk and mitigation of radiation injury make it an important discipline for and beyond cancer care including energy policy, space exploration, national security, and global partnerships.

Theranostic Nanoparticles Loaded with Imaging Probes and Rubrocurcumin for Combined Cancer Therapy by Folate Receptor Targeting.

The combination of different therapeutic modalities is a promising option to combat the recurrence of tumors. In this study, polylactic and polyglycolic acid nanoparticles were used for the simultaneous delivery of a boron-curcumin complex (RbCur) and an amphiphilic gadolinium complex into tumor cells with the aim of performing boron and gadolinium neutron capture therapy (NCT) in conjunction with the additional antiproliferative effects of curcumin. Furthermore, the use of Gd complexes allows magnetic resonance imaging (MRI) assessment of the amount of B and Gd internalized by tumor cells. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles were targeted to ovarian cancer (IGROV-1) cells through folate receptors, by including in the formulation a PEGylated phospholipid functionalized with the folate moiety. NCT was performed on IGROV-1 cells internalizing 6.4 and 78.6 µg g-1 of 10 B and 157 Gd, respectively. The synergic action of neutron treatment and curcumin cytotoxicity was shown to result in a significant therapeutic improvement.

In vivo evaluation of neutron capture therapy effectivity using calcium phosphate-based nanoparticles as Gd-DTPA delivery agent.

PURPOSE: A more immediate impact for therapeutic approaches of current clinical research efforts is of major interest, which might be obtained by developing a noninvasive radiation dose-escalation strategy, and neutron capture therapy represents one such novel approach. Furthermore, some recent researches on neutron capture therapy have focused on using gadolinium as an alternative or complementary for currently used boron, taking into account several advantages that gadolinium offers. Therefore, in this study, we carried out feasibility evaluation for both single and multiple injections of gadolinium-based MRI contrast agent incorporated in calcium phosphate nanoparticles as neutron capture therapy agent. METHODS: In vivo evaluation was performed on colon carcinoma Col-26 tumor-bearing mice irradiated at nuclear reactor facility of Kyoto University Research Reactor Institute with average neutron fluence of 1.8 × 10(12) n/cm(2). Antitumor effectivity was evaluated based on tumor growth suppression assessed until 27 days after neutron irradiation, followed by histopathological analysis on tumor slice. RESULTS: The experimental results showed that the tumor growth of irradiated mice injected beforehand with Gd-DTPA-incorporating calcium phosphate-based nanoparticles was suppressed up to four times higher compared to the non-treated group, supported by the results of histopathological analysis. CONCLUSION: The results of antitumor effectivity observed on tumor-bearing mice after neutron irradiation indicated possible effectivity of gadolinium-based neutron capture therapy treatment.

[Current situation and future prospects of radiotherapy for malignant gliomas].

Prognosis of malignant gliomas remains poor, although adjuvant radiotherapy increases survival time. To improve treatment outcomes, high-precision radiotherapy techniques such as three-dimensional conformal radiotherapy, stereotactic irradiation, intensity modulated radiotherapy, and charged particle radiotherapy have been developed for dose distribution optimization and dose escalation. Improvements in clinical outcomes with these new treatment strategies have been reported; however, the efficacy of these treatment strategies has not yet been verified in randomized trials. Further development of radiation delivery techniques, including boron neutron capture therapy, and ways of achieving more adequate target volume delineation using modern multimodality imaging technology are currently being intensively investigated to further improve patient outcomes.

Formulation considerations of gadolinium lipid nanoemulsion for intravenous delivery to tumors in neutron-capture therapy.

The effects of the formulation and particle composition of gadolinium (Gd)-containing lipid nanoemulsion (Gd-nanoLE) on the biodistribution of Gd after its intravenous (IV) injection in D(1)-179 melanoma-bearing hamsters were evaluated for its application in cancer neutron-capture therapy. Gd-nanoLEs whose particles had an oily core (soybean oil, ethyl oleate, lipiodol, or triolein) and a surface layer of hydrogenated phosphatidylcholine, gadolinium-diethyl-enetriaminepentaacetic acid-distearylamide, and a cosurfactant (Myrj 53, Brij 700, or HCO-60) were prepared by a thin-layer hydration-sonication method. Biodistribution data revealed that Brij 700 and HCO-60 prolonged the retention of Gd in the blood and enhanced its accumulation in tumors. Among the core components employed, soybean oil yielded the highest Gd concentration in the blood and tumor and the lowest in the liver and spleen. Gd-nanoLEs with a Gd content of 1.5-4.5 mg/ml could be formulated by using HCO-60 and soybean oil at a constant oil-to-water ratio, and by enriching Gd in the surface layer with the particle size maintained below 100 nm. When each Gd-nanoLE was IV injected once or twice at a 24-h interval, the Gd concentration in the tumor correlated well with the total dose of Gd, and it reached a maximum of 189 microg/g wet tumor. This maximum Gd level was greater than the limit required for significantly suppressing tumor growth in neutron-capture therapy.

Approach to magnetic neutron capture therapy.

PURPOSE: The method of magnetic neutron capture therapy can be described as a combination of two methods: magnetic localization of drugs using magnetically targeted carriers and neutron capture therapy itself. METHODS AND MATERIALS: In this work, we produced and tested two types of particles for such therapy. Composite ultradispersed ferro-carbon (Fe-C) and iron-boron (Fe-B) particles were formed from vapors of respective materials. RESULTS: Two-component ultradispersed particles, containing Fe and C, were tested as magnetic adsorbent of L-boronophenylalanine and borax and were shown that borax sorption could be effective for creation of high concentration of boron atoms in the area of tumor. Kinetics of boron release into the physiologic solution demonstrate that ultradispersed Fe-B (10%) could be applied for an effective magnetic neutron capture therapy. CONCLUSION: Both types of the particles have high magnetization and magnetic homogeneity, allow to form stable magnetic suspensions, and have low toxicity.

Neutron fibres and possible applications to NCT.

We summarize previous researches regarding neutron guides of small transverse cross-section (neutron fibres), smaller than those of the standard hollow guides and collimators employed currently. Those studies may not be widely known in the neutron capture therapy (NCT) community, but they may be interesting for it. Such neutron fibres could allow to deliver and concentrate neutron beams selectively in regions of size smaller than 1mm. We present new estimates and point out and discuss some new possible specific applications of those neutron fibres, which would not replace standard NCT but could supplement it. Thus, we entertain the possibility that neutron fibres could be useful for additional therapies (in typical NCT durations) of: (i) rather small tumours, (ii) thin borders of tumours. The use of these neutron fibres could reduce the undesirable delivery of radiation to healthy tissue around regions with malignant tissue.

The medical-irradiation characteristics for neutron capture therapy at the Heavy Water Neutron Irradiation Facility of Kyoto University Research Reactor.

At the Heavy Water Neutron Irradiation Facility of the Kyoto University Research Reactor, the mix irradiation of thermal and epi-thermal neutrons, and the solo irradiation of epi-thermal neutrons are available additionally to the thermal neutron irradiation, and then the neutron capture therapy (NCT) at this facility became more flexible, after the update in 1996. The estimation of the depth dose distributions in NCT clinical irradiation, were performed for the standard irradiation modes of thermal, mixed and epi-thermal neutrons, from the both sides of experiment and calculation. On the assumption that the 10B concentration in tumor part was 40 ppm and the ratio of tumor to normal tissue was 3.5, the advantage depth were estimated to 5.4, 6.0, and 8.0, for the respective standard irradiation modes. It was confirmed that the various irradiation conditions can be selected according to the target-volume conditions, such as size, depth, etc. Besides, in the viewpoint of the radiation shielding for patient, it was confirmed that the whole-body exposure is effectively reduced by the new clinical collimators, compared with the old one.

Controllability of depth dose distribution for neutron capture therapy at the Heavy Water Neutron Irradiation Facility of Kyoto University Research Reactor.

The updating construction of the Heavy Water Neutron Irradiation Facility of the Kyoto University Research Reactor has been performed from November 1995 to March 1996 mainly for the improvement in neutron capture therapy. On the performance, the neutron irradiation modes with the variable energy spectra from almost pure thermal to epi-thermal neutrons became available by the control of the heavy-water thickness in the spectrum shifter and by the open-and-close of the cadmium and boral thermal neutron filters. The depth distributions of thermal, epi-thermal and fast neutron fluxes were measured by activation method using gold and indium, and the depth distributions of gamma-ray absorbed dose rate were measured using thermo-luminescent dosimeter of beryllium oxide for the several irradiation modes. From these measured data, the controllability of the depth dose distribution using the spectrum shifter and the thermal neutron filters was confirmed.

Dose distributions in a human head phantom for neutron capture therapy using moderated neutrons from the 2.5 meV proton-7Li reaction or from fission of 235U.

The feasibility of neutron capture therapy (NCT) using an accelerator-based neutron source of the 7Li(p,n) reaction produced by 2.5 MeV protons was investigated by comparing the neutron beam tailored by both the Hiroshima University radiological research accelerator (HIRRAC) and the heavy water neutron irradiation facility in the Kyoto University reactor (KUR-HWNIF) from the viewpoint of the contamination dose ratios of the fast neutrons and the gamma rays. These contamination ratios to the boron dose were estimated in a water phantom of 20 cm diameter and 20 cm length to simulate a human head, with experiments by the same techniques for NCT in KUR-HWNIF and/or the simulation calculations by the Monte Carlo N-particle transport code system version 4B (MCNP-4B). It was found that the 7Li(p,n) neutrons produced by 2.5 MeV protons combined with 20, 25 or 30 cm thick D20 moderators of 20 cm diameter could make irradiation fields for NCT with depth-dose characteristics similar to those from the epithermal neutron beam at the KUR-HWNIF.

Experimental verification of improved depth-dose distribution using hyper-thermal neutron incidence in neutron capture therapy.

We have proposed the utilization of 'hyper-thermal neutrons' for neutron capture therapy (NCT) from the viewpoint of the improvement in the dose distribution in a human body. In order to verify the improved depth-dose distribution due to hyper-thermal neutron incidence, two experiments were carried out using a test-type hyper-thermal neutron generator at a thermal neutron irradiation field in Kyoto University Reactor (KUR), which is actually utilized for NCT clinical irradiation. From the free-in-air experiment for the spectrum-shift characteristics, it was confirmed that the hyper-thermal neutrons of approximately 860 K at maximum could be obtained by the generator. From the phantom experiment, the improvement effect and the controllability for the depth-dose distribution were confirmed. For example, it was found that the relative neutron depth-dose distribution was about 1 cm improved with the 860 K hyper-thermal neutron incidence, compared to the normal thermal neutron incidence.

Measurements and calculations of thermal neutron fluence rate and neutron energy spectra resulting from moderation of 252Cf fast neutrons: applications for neutron capture therapy.

252Cf is a neutron emitting radioisotope which has promise for both standard brachytherapy and neutron capture enhanced brachytherapy. In this study, experimental measurements and calculations were used to determine the thermal neutron fluence rate, phi(th) [n cm(-2) s(-1) mg(-1)], in the vicinity of 252Cf applicator tube (AT) type sources. Results of these measurements were confirmed with Monte Carlo calculations performed in a distributed manner on multiple workstations using MCNP. Three studies were executed: (1) relative phi(th) as a function of distance from a 252Cf AT source in an A-150 tissue equivalent plastic phantom using thermoluminescent dosimeters (TLDs) of varying 6Li/Li enrichment, (2) phi(th) measured with gold foils in a 114 liter water phantom 5 cm from two 252Cf AT sources, and (3) calculations of the impact of phantom material composition (e.g., A-150, water, brain, muscle) on phi(th) from moderated 252Cf fast neutrons. TLD results and Monte Carlo calculations in A-150 of relative phi(th) typically agreed within 1% and at most differed by 3% for distances from 1 to 6 cm. Foil measurements followed the ASTM E 262-86e protocol, and the ratio of activated plain and Cd encased gold foils (7.31) agreed well with the calculated ratio (7.26). Measured phi(th) at 5 cm (1.70+/-0.10 x 10(7) n cm(-2) s(-1) mg(-1)) was 10% greater than that determined using MCNP (1.55+/-0.12 x 10(7) n cm(-2) s(-1) mg(-1)), but was within the combined uncertainties. Compared with A-150 at a distance of 1 cm, phi(th) was 20%, 22%, and 32% less for water, brain, and muscle, respectively; these ratios decreased to 16%, 16%, and 24% less, respectively, at a distance of 5 cm from the source in a 15 cm diameter phantom. Comparisons of these results generally agreed with those in the literature for a value of 2 x 10(7) n cm(-2) s(-1) mg(-1) in water at 3 cm.

Relaxation properties of a dual-labeled probe for MRI and neutron capture therapy.

Pharmaceutical agents labeled with both boron and gadolinium have potential applications in both boron neutron capture therapy (NCT) and magnetic resonance imaging. Pre- and post-injection T1 maps provide a method for the indirect measurement of the gadolinium and boron concentrations that can then be used in NCT treatment planning. This requires an understanding of the relaxation properties of the agent. In this paper we present an analysis of the relaxation properties of a dual boron and gadolinium agent, Gd (III)-diethylenetriaminepentaacetate-carborane [Gd (III)-DTPA-carborane], in vitro in the presence and absence of serum albumin. The nuclear magnetic relaxation dispersion profile of solutions containing albumin obtained with a field cycling relaxometer exhibit a peak in the frequency range from 8 to 50 MHz. This indicates a long rotational correlation time relative to the solution without serum albumin. Results from other experiments indicate that this peak results from the binding of Gd (III)-DTPA-carborane derivative to serum albumin. Temperature studies indicate that the water proton relaxation efficiency of bound agent is limited by the water residence time as the relaxivity increases from 19 +/- 1 to 32.6 +/-; 0.8 (sec.mM)-1 when the temperature is increased from 5 to 35 degrees C.

Boron neutron capture therapy for glioblastoma: improvement of boron biodistribution by hyaluronidase.

Boron neutron capture therapy (BNCT) represents a highly promising therapeutic alternative for the treatment of the most common malignant brain tumor, glioblastoma multiforme. Both the efficacy and safety of BNCT are greatly dependent on the pattern of 10B biodistribution. The present study investigates the influence of systemic hyaluronidase applied in combination with Na2B12H11SH (BSH), a boron carrier used in current clinical trials. The application of hyaluronidase was associated with a statistically significant improvement in the tumor/blood boron concentration ratio which suggests that hyaluronidase is capable of enhancing the therapeutic potential of BSH.

Physical and biological doses produced from neutron capture in a 235U foil.

As a follow-on study to the feasibility of neutron capture therapy (NCT) with 235U brachytherapy seeds, physical doses were calculated and measured for the radiation from a 235U foil in a lucite phantom which was irradiated at the epithermal neutron irradiation port of the Brookhaven Medical Research Reactor. In addition, cell survival experiments were performed to obtain the relative biological effectiveness (RBE) for the neutron part of the radiation. The calculated absorbed doses agree with the measured ones. From cell survival experiments, it is deduced that the fission neutrons from the 235U foil have a RBE of 3.0 while the fast neutrons in the beam have a RBE of 3.8. Also observed is that, with the cells 7 mm from the foil, a significant amount of absorbed dose comes from the beta rays of 235U fission events. This absorbed dose from beta rays is a significant addition to the therapeutic dose. Due to the limited ranges of beta rays in tissue, this absorbed dose is restricted to the vicinity of the foil. This is the first demonstration of beta rays as part of NCT.

Uranium-loaded apoferritin with antibodies attached: molecular design for uranium neutron-capture therapy.

A method is described to deliver 235U to tumors; the isotope would then be fissioned by incident neutrons, producing localized lethal radiation sufficient for therapy. Apoferritin was loaded with an average of approximately 800 238U atoms per molecule. Stability of the loaded apoferritin in solution was improved, so that only 8% loss of uranium occurred after 8 days at pH 7. Fab' antibody fragments were covalently attached to the uranium-loaded apoferritin, and the immunoreactivity of the conjugate was 92% of that for antibody alone. Such bio-uranium constructions should provide significant advantages over boronated antibodies to meet the requirements for clinical neutron-capture therapy.