Synthesis and biological evaluation of new boron-containing chlorin derivatives as agents for both photodynamic therapy and boron neutron capture therapy of cancer

New boron-containing chlorin derivatives 9 and 13 as agents for both photodynamic therapy (PDT) and boron neutron capture therapy (BNCT) of cancer were synthesized from photoprotoporphyrin IX dimethyl ester (2) and l-4-boronophenylalanine-related compounds. The in vivo biodistribution and clearance of 9 and 13 were investigated in tumor-bearing mice. The time to maximum accumulation of compound 13 in tumor tissue was one-fourth of that of compound 9, and compound 13 showed rapid clearance from normal tissues within 24 h after injection. The in vivo therapeutic efficacy of PDT using 13 was evaluated by measuring tumor growth rates in tumor-bearing mice with 660 nm light-emitting diode irradiation at 3 h after injection of 13. Tumor growth was significantly inhibited by PDT using 13. These results suggested that 13 might be a good candidate for both PDT and BNCT of cancer.     

Prompt gamma ray imaging for verification of proton boron fusion therapy: A Monte Carlo study

PurposeThe purpose of this study was to verify acquisition feasibility of a single photon emission computed tomography image using prompt gamma rays for proton boron fusion therapy (PBFT) and to confirm an enhanced therapeutic effect of PBFT by comparison with conventional proton therapy without use of boron.MethodsMonte Carlo simulation was performed to acquire reconstructed image during PBFT. We acquired percentage depth dose (PDD) of the proton beams in a water phantom, energy spectrum of the prompt gamma rays, and tomographic images, including the boron uptake region (BUR; target). The prompt gamma ray image was reconstructed using maximum likelihood expectation maximisation (MLEM) with 64 projection raw data. To verify the reconstructed image, both an image profile and contrast analysis according to the iteration number were conducted. In addition, the physical distance between two BURs in the region of interest of each BUR was measured.ResultsThe PDD of the proton beam from the water phantom including the BURs shows more efficient than that of conventional proton therapy on tumour region. A 719 keV prompt gamma ray peak was clearly observed in the prompt gamma ray energy spectrum. The prompt gamma ray image was reconstructed successfully using 64 projections. Different image profiles including two BURs were acquired from the reconstructed image according to the iteration number.ConclusionWe confirmed successful acquisition of a prompt gamma ray image during PBFT. In addition, the quantitative image analysis results showed relatively good performance for further study.     

Towards boron neutron capture therapy: The formulation and preliminary in vitro evaluation of liposomal vehicles for the therapeutic delivery of the dequalinium salt of bis-nido-carborane

Liposomes of phosphatidylcholine or of dimyristoylphosphatidylcholine that incorporate bis-nido-carborane dequalinium salt are stable in physiologically relevant media and have in vitro toxicity profiles that appear to be compatible with potential therapeutic applications. These features render the structures suitable candidate boron-delivery vehicles for evaluation in the boron neutron capture therapy of cancer.     

Intracellular boron localization and uptake in cell cultures using imaging secondary ion mass spectrometry (ion microscopy) for neutron capture therapy for cancer.

Quantitative ion microscopy of freeze-fractured, freeze-dried cultured cells is a technique for single cell and subcellular elemental analysis. This review describes the technique and its usefulness in determining the uptake and subcellular distribution of the boron from boron neutron capture therapy drugs.     

A universal approach to the synthesis of carbohydrate conjugates of polyhedral boron compounds as potential agents for boron neutron capture therapy

A universal approach to the synthesis of carbohydrate conjugates with polyhedral boron compounds (PBCs) was developed. Oligosaccharide derivatives with amino group in aglycone moiety can be conjugated with PBC carboxy derivatives using N-methyl-N-(4,6-dimethoxy-1,3,5-triazin-2-yl)morpholinium chloride as a condensing agent. Both N-and O-glycosides differing in the conformation mobility around the glycoside bond were shown to be useful as oligosaccharides with a functional group in the aglycone moiety. This allows the application of this approach to the synthesis of PBC conjugates with a wide range of oligosaccharides isolated from natural sources can be transformed into N-glycosides with a functional group in aglycone. The approach was tested by conjugation of the carboxy derivatives of ortho-carborane and dodecaborate anion with lactose as a model oligosaccharide. Lactose, an easily available disaccharide, is a ligand of lectins expressed on the surface of melanoma cells. The approach suggested is the first example of the synthesis of such conjugates that does not require protective groups for the carbohydrate residue. It is especially important for obtaining dodecaborate-carbohydrate conjugates for which the removal of protective groups is often a non-trivial task.     

Design and synthesis of boron containing monosaccharides by the hydroboration of d-glucal for use in boron neutron capture therapy (BNCT)

Boron neutron capture therapy (BNCT) is one of the radiotherapies that involves the use of boron-containing compounds for the treatment of cancer. Boron-10 (¹⁰B) containing compounds that can accumulate in tumor tissue are expected to be suitable agents for BNCT. We report herein on the design and synthesis of some new BNCT agents based on a d-glucose scaffold, since glycoconjugation has been recognized as a useful strategy for the specific targeting of tumors. To introduce a boryl group into a d-glucose scaffold, we focused on the hydroboration of d-glucal derivatives, which have a double bond between the C1 and C2 positions. It was hypothesized that a C–B bond could be introduced at the C2 position of d-glucose by the hydroboration of d-glucal derivatives and that the products could be stabilized by conversion to the corresponding boronic acid ester. To test this hypothesis, we prepared some 2-boryl-1,2-dideoxy-d-glucose derivatives as boron carriers and evaluated their cytotoxicity and cellular uptake activity to cancer cells, especially under hypoxic conditions.     

Influence of beam incidence and irradiation parameters on stray neutron doses to healthy organs of pediatric patients treated for an intracranial tumor with passive scattering proton therapy

PurposeIn scattering proton therapy, the beam incidence, i.e. the patient’s orientation with respect to the beam axis, can significantly influence stray neutron doses although it is almost not documented in the literature.MethodsMCNPX calculations were carried out to estimate stray neutron doses to 25 healthy organs of a 10-year-old female phantom treated for an intracranial tumor. Two beam incidences were considered in this article, namely a superior (SUP) field and a right lateral (RLAT) field. For both fields, a parametric study was performed varying proton beam energy, modulation width, collimator aperture and thickness, compensator thickness and air gap size.ResultsUsing a standard beam line configuration for a craniopharyngioma treatment, neutron absorbed doses per therapeutic dose of 63 μGy Gy⁻¹ and 149 μGy Gy⁻¹ were found at the heart for the SUP and the RLAT fields, respectively. This dose discrepancy was explained by the different patient’s orientations leading to changes in the distance between organs and the final collimator where external neutrons are mainly produced. Moreover, investigations on neutron spectral fluence at the heart showed that the number of neutrons was 2.5 times higher for the RLAT field compared against the SUP field. Finally, the influence of some irradiation parameters on neutron doses was found to be different according to the beam incidence.ConclusionBeam incidence was thus found to induce large variations in stray neutron doses, proving that this parameter could be optimized to enhance the radiation protection of the patient.     

Beam characterisation studies of the 62 MeV proton therapy beamline at the Clatterbridge Cancer Centre

The Clatterbridge Cancer Centre (CCC) in the United Kingdom is the world’s first hospital proton beam therapy facility, providing treatment for ocular cancers since 1989. A 62 MeV beam of protons is produced by a Scanditronix cyclotron and transported through a passive delivery system. In addition to the long history of clinical use, the facility supports a wide programme of experimental work and as such, an accurate and reliable simulation model of the treatment beamline is highly valuable. However, as the facility has seen several changes to the accelerator and beamline over the years, a comprehensive study of the CCC beam dynamics is needed to firstly examine the beam optics. An extensive analysis was required to overcome facility related constraints to determine fundamental beamline parameters and define an optical lattice written with the Methodical Accelerator Design (MAD-X) and the particle tracking Beam Delivery Simulation (BDSIM) code. An optimised case is presented and simulated results of the optical functions, beam distribution, losses and the transverse rms beam sizes along the beamline are discussed. Corresponding optical and beam information was used in TOPAS to simulate transverse beam profiles and compared to EBT3 film measurements. We provide an overview of the magnetic components, beam transport, cyclotron, beam and treatment related parameters necessary for the development of a present day optical model of the facility. This work represents the first comprehensive study of the CCC facility to date, as a basis to determine input beam parameters to accurately simulate and completely characterise the beamline.     

Validation and practical implementation of seated position radiotherapy in a commercial TPS for proton therapy

PurposeThis work aims to validate new 6D couch features and their implementation for seated radiotherapy in RayStation (RS) treatment planning system (TPS).Materials and methodsIn RS TPS, new 6D couch features are (i) chair support device, (ii) patient treatment option of “Sitting: face towards the front of the chair”, and (iii) patient support pitch and roll capabilities. The validation of pitch and roll was performed by comparing TPS generated DRRs with planar x-rays. Dosimetric tests through measurement by 2D ion chamber array were performed for beams created with varied scanning and treatment orientation and 6D couch rotations. For the implementation of 6D couch features for treatments in a seated position, the TPS and oncology information system (Mosaiq) settings are described for a commercial chair. An end-to-end test using an anthropomorphic phantom was performed to test the complete workflow from simulation to treatment delivery.ResultsThe 6D couch features were found to have a consistent implementation that met IEC 61712 standard. The DRRs were found to have an acceptable agreement with planar x-rays based on visual inspection. For dose map comparison between measured and calculated, the gamma index analysis for all the beams was >95% at a 3% dose-difference and 3 mm distance-to-agreement tolerances. For an end-to end-testing, the phantom was successfully set up at isocenter in the seated position and treatment was delivered.ConclusionsChair-based treatments in a seated position can be implemented in RayStation through the use of newly released 6D couch features.     

Synthesis of closo-Dodecaboryl Lipids and their Liposomal Formation for Boron Neutron Capture Therapy

High accumulation and selective delivery of boron into tumor tissues are the most important requirements to achieve efficient neutron capture therapy of cancers. We focused on liposomal boron delivery system to achieve a large amount of boron delivery to tumor. We succeeded in the synthesis of the double-tailed boron cluster lipids 4a–c and 5a–c, which has a B₁₂H₁₁S-moiety as a hydrophilic function, by S-alkylation of B₁₂H₁₁SH with bromoacetyl and chloroacetocarbamate derivatives of diacylglycerols. Size distribution of liposomes prepared from the boron cluster lipid 4b, dimyristoylphosphatidylcholine, polyethyleneglycol-conjugated distearoylphosphatidylethanolamine, and cholesterol was determined as 100 nm in diameter by an electrophoretic light scattering spectrophotometer. Calcein-encapsulation experiments revealed that these boronated liposomes are stable at 37 °C in fetal bovine serum solution for 24 h.     

Experimental benchmarking of RayStation proton dose calculation algorithms inside and outside the target region in heterogeneous phantom geometries

PurposeThe aim of the presented study was to complement existing literature on benchmarking proton dose by comparing dose calculations with experimental measurements in heterogeneous phantom. Points of interest inside and outside the target were considered to quantify the magnitude of calculation uncertainties in current and previous proton therapy practice that might especially have an impact on the dose in organs at risk (OARs).MethodsThe RayStation treatment planning system (RaySearch Laboratories), offering two dose calculation algorithms for pencil beam scanning in proton therapy, i.e., Pencil Beam (PB) and Monte Carlo (MC), was utilized. Treatment plans for a target located behind the interface of the heterogeneous tissues were generated. Dose measurements within and behind the target were performed in a water phantom with embedded slabs of various tissue equivalent materials and 24 PinPoint ionization chambers (PTW). In total 12 test configurations encompassing two different target depths, oblique beam incidence of 30 degrees and range shifter, were considered.ResultsPB and MC calculated doses agreed equally well with the measurements for all test geometries within the target, including the range shifter (mean dose differences ± 3%). Outside the target, the maximum dose difference of 9% (19%) was observed for MC (PB) for the oblique beam incidence and inserted range shifter.ConclusionThe accuracy of MC dose algorithm was superior compared to the PB algorithm, especially outside the target volumes. MC based dose calculation should therefore be preferred in treatment scenarios with heterogeneities, especially to reduce clinically relevant uncertainties for OARs.     

Out-of-field doses from secondary radiation produced in proton therapy and the associated risk of radiation-induced cancer from a brain tumor treatment

PurposeTo determine out-of-field doses produced in proton pencil beam scanning (PBS) therapy using Monte Carlo simulations and to estimate the associated risk of radiation-induced second cancer from a brain tumor treatment.MethodsSimulations of out-of-field absorbed doses were performed with MCNP6 and benchmarked against measurements with tissue-equivalent proportional counters (TEPC) for three irradiation setups: two irradiations of a water phantom using proton energies of 78–147 MeV and 177–223 MeV, and one brain tumor irradiation of a whole-body phantom. Out-of-field absorbed and equivalent doses to organs in a whole-body phantom following a brain tumor treatment were subsequently simulated and used to estimate the risk of radiation-induced cancer. Additionally, the contribution of absorbed dose originating from radiation produced in the nozzle was calculated from simulations.ResultsOut-of-field absorbed doses to the TEPC ranged from 0.4 to 135 µGy/Gy. The average deviation between simulations and measurements of the water phantom irradiations was about 17%. The absorbed dose contribution from radiation produced in the nozzle ranged between 0 and 70% of the total dose; the contribution was however small in absolute terms. The absorbed and equivalent doses to the organs ranged between 0.2 and 60 µGy/Gy and 0.5–151 µSv/Gy. The estimated lifetime risk of radiation-induced second cancer was approximately 0.01%.ConclusionsThe agreement of out-of-field absorbed doses between measurements and simulations was good given the sources of uncertainties. Calculations of out-of-field organ doses following a brain tumor treatment indicated that proton PBS therapy of brain tumors is associated with a low risk of radiation-induced cancer.     

Beam angle optimization using angular dependency of range variation assessed via water equivalent path length (WEPL) calculation for head and neck proton therapy

PurposeTo investigate angular sensitivity of proton range variation due to anatomic change in patients and patient setup error via water equivalent path length (WEPL) calculations.MethodsProton range was estimated by calculating WEPL to the distal edge of target volume using planning CT (pCT) and weekly scatter-corrected cone-beam CT (CBCT) images of 11 head and neck patients. Range variation was estimated as the difference between the distal WEPLs calculated on pCT and scatter-corrected CBCT (cCBCT). This WEPL analysis was performed every five degrees ipsilaterally to the target. Statistics of the distal WEPL difference were calculated over the distal area to compare between different beam angles. Physician-defined contours were used for the WEPL calculation on both pCT and cCBCT, not considering local deformation of target volume. It was also tested if a couch kick (10°) can mitigate the range variation due to anatomic change and patient setup error.ResultsFor most of the patients considered, median, 75% quantile, and 95% quantile of the distal WEPL difference were largest for posterior oblique angles, indicating a higher chance of overdosing normal tissues at distal edge with these angles. Using a couch kick resulted in decrease in the WEPL difference for some posterior oblique angles.ConclusionsIt was demonstrated that the WEPL change has angular dependency for the cohort of head and neck cancer patients. Selecting beam configuration robust to anatomic change in patient and patient setup error may improve the treatment outcome of head and neck proton therapy.     

Evaluating the usefulness of the direct density reconstruction algorithm for intensity modulated and passively scattered proton therapy: Validation using an anthropomorphic phantom

PurposeAccurate calculation of the proton beam range inside a patient is an important topic in proton therapy. In recent times, a computed tomography (CT) image reconstruction algorithm was developed for treatment planning to reduce the impact of the variation of the CT number with changes in imaging conditions. In this study, we investigated the usefulness of this new reconstruction algorithm (DirectDensity™: DD) in proton therapy based on its comparison with filtered back projection (FBP).MethodsWe evaluated the effects of variations in the X-ray tube potential and target size on the FBP- and DD-image values and investigated the usefulness of the DD algorithm based on the range variations and dosimetric quantity variations.ResultsFor X-ray tube potential variations, the range variation in the case of FBP was up to 12.5 mm (20.8%), whereas that of DD was up to 3.3 mm (5.6%). Meanwhile, for target size variations, the range variation in the case of FBP was up to 2.2 mm (2.5%), whereas that of DD was up to 0.9 mm (1.4%). Moreover, the variations observed in the case of DD were smaller than those of FBP for all dosimetric quantities.ConclusionThe dose distributions obtained using DD were more robust against variations in the CT imaging conditions (X-ray tube potential and target size) than those obtained using FBP, and the range variations were often less than the dose calculation grid (2 mm). Therefore, the DD algorithm is effective in a robust workflow and reduces uncertainty in range calculations.