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Organic-Gelatin-Free Nanocomposite Fricke Gel Dosimeter Takuya Maeyama,*,†,‡ Nobuhisa Fukunishi,† Kenichi L. Ishikawa,§,† Kazuaki Fukasaku,∥,⊥ and Shigekazu Fukuda# †

RIKEN Nishina Center for Accelerator-Based Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan Department of Chemistry, School of Science, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan § Department of Nuclear Engineering and Management, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan ∥ Department of Neurosurgery, Himon’ya Hospital, 2-9-5 Minami, Meguro-ku, Tokyo 152-0013, Japan ⊥ Advanced Center for Computing and Communication, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan # Radiation Quality Control Section, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan ‡

S Supporting Information *

ABSTRACT: We report a nanocomposite Fricke gel (NC-FG) dosimeter prepared using only Fe2+ and nanoclay in water, without any organic gelling agents. This dosimeter gels due to its thixotropic properties and exhibits linear energy transfer (LET)-independent radiological properties under carbon ion beam irradiation. The radiation sensitivity of this dosimeter was 1.8 [s−1 kGy−1], which is three times higher than that reported previously (0.6 [s−1 kGy−1]) for a similar dosimeter containing gelatin. The Fe3+ yield was determined to be 0.19 μmol/J by evaluating the difference in spin−lattice relaxivity between Fe3+ and Fe2+. A further increase in the radiation sensitivity was observed upon addition of the hydrated electron scavenger N2O, suggesting the reduction of Fe3+ by a hydrated electron. LET-dependent variations of the contributions of OH radicals and hydrated electrons compensate each other in the oxidation yield of NC-FG. This is the main mechanism of the suppression of LET effects in the Bragg peak compared to conventional Fricke dosimeters. The radiation-induced oxidation yield G(Fe3+) can be described by the stoichiometric equation {G(Fe3+) = G(OH) − G(eaq−) + 2G(H2O2) + G(H)} with the reported LET dependence of the primary yield of water decomposition radicals. The calculated results are in approximate agreement with the absolute value of the experimental oxidation yield of NC-FG. The effects of the addition of small amounts of radical scavengers (nitrate, selenate, or cadmium) are also evaluated. The sensitivity was divided into two types, and influences of intermediate radicals after scavenging reaction are indicated.

■

recombinations of radical products (i.e., OH, eaq−, and H) that contribute to radiation-induced chemical reactions.10 A Fricke gel dosimeter prepared using an aqueous Fricke solution and a gel matrix such as gelatin or agarose also shows LET dependence.11 However, we have recently found that the addition of a small amount of nanosized clay particles and deaeration of a conventional Fricke gel dramatically alter the sensitivity of the gel dosimeter so that the dosimeter exhibits LET-independent dose response.12 This gel dosimeter, called a nanocomposite Fricke gel (NC-FG) dosimeter, is the only dosimeter to date capable of measuring the 3D dose distribution of heavy ion beam irradiation; all other types of 3D dosimeters, to the best of our knowledge, exhibit decreased sensitivity as the LET value increases.2 Subsequently, we have

INTRODUCTION A compact rotating gantry with a carbon ion pencil beam capable of three-dimensional (3D) scanning has been developed for advanced cancer radiotherapy to provide a higher contrast dose distribution.1 A 3D dosimeter for heavy ion beam irradiation is therefore needed to verify complex dose distributions in tissue-equivalent material.2 A 3D chemical dosimeter using a gel matrix has been proposed by Gore,3 in which the amount of radiation-induced chemical reaction products stored in the gel matrix provides information on the spatial dose distribution. The 3D dose distribution can be extracted from measurements of irradiated gel samples using a 3D imaging technique such as magnetic resonance imaging (MRI).4,5 On the other hand, the practical application of a gel dosimeter to heavy ion beam dosimetry is complicated by the degradation in sensitivity as a function of linear energy transfer (LET).6−9 This LET dependence of the radiation sensitivity is well-known as LET effects that are caused by radical−radical © 2017 American Chemical Society

Received: November 28, 2016 Revised: February 16, 2017 Published: March 22, 2017 4238

DOI: 10.1021/acs.jpcb.6b11936 J. Phys. Chem. B 2017, 121, 4238−4246

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The Journal of Physical Chemistry B Table 1. Prepared Gel Samples and Experimental Conditions scavenging capacity/s−1 additive

concn (mM)

eaq−

OH

purpose

postirradiationb (days)

deaerated N2O H2 NO3− SeO42−

(Fe2+) N2O gas H2 gas NaNO3 Na2SeO4

1.2 × 105 2.3 × 108

3.4 × 105

Cd2+

CdSO4

1 25 0.8 1 1 7 1

reference eaq− → OH (100%) OH → H (9%) eaq− (99%) eaq− (92%) eaq− (99%) eaq− (100%)

18, 7, and 4 7 7 7 7 4 7

gel samples

a

3.2 × 104 9.2 1.4 9.8 4.7

× × × ×

6

10 106 106 107

4.2 × 102 2.9 × 103

a

All gel samples were prepared from 2% (w/w) nanoclay and 1 mM ammonium iron(II) sulfate hexahydrate solution under deaerated conditions. b The postirradiation time of the MRI measurement is shown for each experiment. Experiments using deaerated NC-FG were repeated three times. One experiment was designed to determine the dose rate and dose fractionation effect.

This was added to the clay dispersion under atmospheric conditions and immediately agitated using the rotation/ revolution vacuum mixer for 20 min using the same mixing conditions as those above. The resulting clear colorless suspension was divided and sealed into five Pyrex glass tubes (Iwaki Glass Co, 9827TST32-230F: 32 mm outer diameter and 23 cm long, Japan) under a pure N2 atmosphere in a glovebox. These glass tubes containing NC-FG were reagitated using a special jig (EME Corp.) and the rotation/revolution vacuum mixer for 3 min at 1200 rpm/600 rpm under atmospheric conditions (−0 hPa gauge pressure). This NC-FG sample was called deaerated NC-FG and used as a reference for comparing radiological properties. NC-FG samples containing one of six additives were also prepared, as summarized in Table 1. Addition of Nitrous Oxide (N2O). N2O-saturated NC-FG samples were obtained by bubbling N2O gas through ultrapure water for 30 min before mixing in the nanoclay. Addition of Hydrogen (H2) Gas. H2-saturated NC-FG samples were prepared by bubbling H2 gas through ultrapure water for 30 min. A H2-saturated clay dispersion was obtained by mixing the dispersion using a powerful magnetic stirrer (Model SW-R300, Nissin, Japan) for 1 h while bubbling H2 gas. Addition of NO3−, SeO42−, and Cd2+. The additives 1 mM sodium nitrate, 1 or 7 mM sodium selenate, and 1 mM cadmium sulfate (Wako Chemicals, Osaka, Japan, CAS No. 7631-99-4, 13410-01-0, and 7790-84-3, respectively) were added to NC-FG using the rotation/revolution vacuum mixer for 20 min (rotation/revolution = 1200 rpm/600 rpm; N2 purging at a −90 hPa gauge pressure). The subsequent preparation steps were the same as those described above. Heavy Ion Beam Irradiation. The irradiation experiments were performed at the Biological Radiation Port of the Heavy Ion Medical Accelerator in Chiba (HIMAC) at the National Institute of Radiological Sciences (NIRS), Japan. A 12C6+ beam at 290 MeV/u with an irradiation field of 5% lateral dose uniformity with a 10 cm diameter and a 10 Gy/min dose rate was used.18,19 The uniform irradiation field was formed using wobbler magnets and a scatterer. Pyrex glass tubes (outer diameter 32 mm, length 23 cm) containing NC-FG were placed within the uniform irradiation field and irradiated from the bottom surface of the tubes. At the entrance surface of the bottom of the Pyrex glass tubes, the absorbed dose (referred to as the entrance surface dose, ESD hereafter) varied from 0 to 600 Gy. The ESD was calibrated by measuring the dose at the same position as the bottom surface of the sample using a Markus ionization chamber (IC). On the basis of the dose evaluated by this method, the accumulated dose at the entrance surface during sample irradiation can be determined by using a

reported the radiological properties of NC-FG dosimeters prepared using different concentrations of nanoclay, perchloric acid, and ferrous ions under deaerated conditions.13 The features of these NC-FG dosimeters were distinct from those of conventional Fricke gels.14−17 In particular, the radiation sensitivity decreases with decreasing nanoclay concentration in NC-FG, which indicates that the nanoclay is indispensable for the radiation-induced oxidation of Fe2+. In the present study, we report a new NC-FG that gels without any organic gelling agents such as gelatin. Homogeneous samples can be prepared without heating and without air bubbles, using a rotation/revolution mixer. The radiological properties of dosimeters prepared using the resulting thixotropic hydrogel are investigated, including the dose rate and dose fractionation effects as well as the effects of the addition of radical scavengers. The organic-gelatin-free NC-FG exhibits three times higher radiation sensitivity than the previously reported NC-FG (with gelatin)12,13 while retaining the desirable LET-independent dose response. We propose a stoichiometric equation for the radiation-induced oxidation yield G(Fe3+) and identify the reduction of Fe3+ by a hydrated electron as a plausible cause underlying the LET-independent dose response.

■

EXPERIMENTAL SECTION Materials. Organic-gelatin-free NC-FG was prepared from 2% (w/w) nanoclay (synthetic hectorite or Laponite XLG; Na0.7+[Si8Mg5.5Li0.3]O20(OH)4)0.7−, Rockwood Ltd., Widnes, U.K., CAS No. 53320-86-8) and 1 mM ammonium iron(II) sulfate hexahydrate (Mohr’s salt; (NH4)2Fe(SO4)2·6H2O, Fluka, Japan, CAS No. 7783-85-9) solution under deaerated conditions. The NC-FG described here does not contain an organic gelling agent such as gelatin but rather gels with time due to its favorable thixotropic properties. NC-FG (800 g) was prepared as follows. First, ultrapure water (Purelab Flex UV, Elga LabWater, U.K.) was deaerated to an oxygen level of 20 ppb using a membrane deaeration device containing surfactantcompatible degassing modules (EF-002A, DIC Corp. Japan). The concentration of dissolved oxygen in the deaerated water was measured using a low-level dissolved oxygen meter (DO32A, DKK-TOA Corp., Japan). Nanoclay (16 g) was added to 734 mL of deaerated water under atmospheric conditions and immediately agitated using a rotation/revolution vacuum mixer (UFO1.5 model, EME Corp., Japan) for 20 min at 1200 rpm/ 600 rpm (rotation/revolution) and N2 purging at a −90 hPa gauge pressure to obtain a uniform dispersion. Fricke stock solution (50 mL) was prepared by mixing 0.307 g of ammonium iron(II) sulfate hexahydrate and deaerated water. 4239

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added, and the tubes were sealed. All steps were conducted under a pure N2 atmosphere in a glovebox. The contents of the glass tubes were reagitated using the rotation/revolution vacuum mixer for 10 min at 1200 rpm/600 rpm and −0 hPa gauge pressure. The Fe3+ yield due to oxidation of Fe2+ by H2O2 in the five samples was evaluated as described in the previous subsection.

secondary electron monitor installed permanently on the upstream side of the beamline.18,19 The depth−dose profile of this carbon ion beam was also measured using the Markus IC by decreasing the beam energy using a binary filter-type range shifter consisting of plastic (PMMA) plates.20,21 The total thickness of the PMMA can be varied by changing the combination of PMMA plates inserted on the beam axis. The IC dose was measured at each PMMA thickness in terms of the water equivalent thickness. The dose near the Bragg peak was determined with the smallest interval using a 500 μm PMMA plate.8 The irradiation experiment using deaerated NC-FG was performed twice on February 26, 2015 and June 9, 2015 to verify the reproducibility of the measurements for gels prepared on different days. Dose rate effects and dose fractionation effects were also investigated using deaerated NC-FG gel samples during irradiation with a 12C6+ beam at 290 MeV/u with a narrower homogeneous irradiation field (3 cm in diameter) to increase the dose rate up to 60 Gy/min and, using two attenuators, to decrease the dose rate to 30 and 10 Gy/ min. These attenuators were constructed of mesh and were installed in the injection beam (0.1 mm thickness, tantalum, hole diameter 0.1 mm, pitch 1 mm).22 For the narrower homogeneous irradiation field, we also calibrated the absolute dose and the depth−dose profile by the same method described previously. NC-FG samples were irradiated with 200 Gy at 60, 30, and 10 Gy/min. For the fractionation irradiation experiments, deaerated NC-FG was irradiated with 200 Gy in 2 × 100 Gy fractions with a dose rate of 60 Gy/min and an interval of 35 min between doses. MRI Measurements. A 1.5 T MRI scanner (Intera Achieva 1.5T HP Nova Dual Gradient, Philips Medical Systems, Best, The Netherlands) was used to analyze the NC-FG samples. The longitudinal, or spin−lattice relaxation rate, R1 = 1/T1 (s−1) of the NC-FG samples was evaluated using a turbo mixed sequence.23,24 The conditions of the T1 measurements were as follows: TR = 2260 ms; TE1 = 19 ms; TE2 = 100 ms; TI = 500 ms; ETL = 6; pixel spacing = 0.8 mm; number of averages = 6; slice thickness = 10 mm. The matrix size was 448 × 448. The magnetic field was oriented perpendicular to the radiation beam direction of the NC-FG glass samples. The T1 distributions were obtained directly from the PHILIPS software. The postirradiation times of the MRI measurements are shown in Table 1 for each experiment. 3+ Evaluation of the Spin−Lattice Relaxivity rFe of Fe3+. The spin−lattice relaxivity is defined as the enhancement of the spin−lattice relaxation rate R1 per millimolar of iron and thus has units of s−1 mM−1. The gel samples were prepared using 0− 0.55 mM Fe2+ ((NH4)2Fe(SO4)2·6H2O) and 2 wt % nanoclay and were oxidized using 5 or 10 mM H2O2. The concentration of Fe3+ was assumed to be the same as the initial concentration of Fe2+ prepared because H2O2 was present in excess for this 3+ oxidation reaction. Thus, the spin−lattice relaxivity rFe (s−1 mM−1) of Fe3+ was evaluated as a slope of the calibration curve (plot of R1 (s−1) vs [Fe3+] (mM) or [initial Fe2+] (mM)) by measuring gel samples (without irradiation) using the same 1.5 T MRI scanner and the MRI sequence as those employed for the irradiated NC-FG samples. Evaluation of the Direct Oxidation Yield of Fe2+ to Fe3+ in NC-FG by H2O2. Organic-gelatin-free NC-FG containing 1 mM Fe2+ was prepared as described above and divided into five 130 mL Pyrex glass tubes. Then, 1 mL of hydrogen peroxide stock solution (0, 24, 49, 73, or 97 mM) was

■

RESULTS AND DISCUSSION 3+

Evaluation of the Spin−Lattice Relaxivity rFe of Fe3+. The relaxation rate R1 as a function of the initial Fe2+ concentration in nonirradiated NC-FG containing 5 and 10 mM H2O2 is shown in Figure 1. Nearly identical R1 values are

Figure 1. Changes in the relaxation rate R1 vs [Fe3+] used as the calibration curve. Squares and circles represent the values measured using gel samples oxidized using 5 and 10 mM H2O2, respectively. The samples were prepared from 2 wt % nanoclay containing 0−0.55 mM ammonium iron(II) sulfate. The dashed line is a linear fit to the data.

obtained from gels containing 5 or 10 mM H2O2, indicating that the Fe2+ was completely oxidized to Fe3+ by H2O2. Thus, the slope of the curve in Figure 1 corresponds to the spin− 3+ lattice relaxivity of Fe3+ and is found to be rFe = 10.0 s−1 −1 mM . 2+ Although the spin−lattice relaxivity rFe of Fe2+ is difficult to directly measure due to auto-oxidation induced by oxygen 2+ contamination in clay dispersion, one can estimate it as rFe = −1 −1 0.602 s mM by using the calculated value of the spin− ⎛ r Fe3+ (s−1 mM−1) ⎞ lattice relaxivity ratio ⎜ Fe2+ −1 −1 ≅ 16.6⎟ reported in refs 3 ⎝ r (s mM ) ⎠ 25. Then, one can relate the Fe3+ radiolytic yield G(Fe3+) in irradiated samples to the radiation sensitivity δR1(s−1 kGy−1) by the following equation26 1 G(Fe3 +)(μmol J−1 ) = × δR1 × ρ 2+ Fe3 + (r − r Fe ) = 0.106δR1 (s−1 kGy −1)

(1)

where ρ is the mass density of NC-FG and was determined to be 1007 ± 4 kg/m3 using a flask at room temperature. Effects of Reagitating Sealed NC-FG Samples. The MRI images of nonirradiated NC-FG samples either reagitated or not reagitated are shown in Supporting Information Figure S1a,b, respectively. Whereas the nonreagitated sealed NC-FG sample provided an inhomogeneous R1 map (two-dimensional R1 distributions; Figure S1b), this inhomogeneity was effectively eliminated by reagitating the sample (Figure S1a). Consequently, we reagitated all of the sealed NC-FG samples 4240

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Bragg peak region of the carbon ion beam due to an increase in LET. Dose Rate and Fractionation Effects. Depth−R 1 distributions in NC-FG irradiated at different dose rates and dose fractionations are shown in Figure 3. The NC-FG exhibits

used in the experiments. Although NC-FG can be prepared without heating, measurable gelation of NC-FG was observed prior to filling of NC-FG into a Pyrex glass tube, and the gel strength increased with time due to its high thixotropic characteristic. The inhomogeneous R1 map is likely due to the presence of a small amount of contaminating oxygen introduced during the filling step. In addition, the effectiveness of inhomogeneity elimination by reagitation using the rotation/ revolution mixer depended on the degree of gel agitation and on the gel strength, and the inhomogeneity could not be eliminated if the preparation contained more than 2% clay. Radiological Properties of Gelatin-Free NC-FG. The measured R1−depth distributions in the organic-gelatin-free NC-FG dosimeters are shown in Figure 2a. The R1 value at

Figure 3. Depth−R1 distribution in NC-FG with different dose rates and dose fractionation. NC-FG samples irradiated with a 200 Gy ESD in total with three different dose rates (10, 30, and 60 Gy/min) and a dose-fractioned irradiation (2 × 100 Gy) at a dose rate of 60 Gy/min with a 35 min interval between the two fractioned irradiations. All irradiations were conducted using a 290 MeV/u carbon ion beam with a homogeneous irradiation field of 3 cm in diameter.

practically no effects of dose rate and dose fractionation under the conditions investigated in the present study. The average radiation sensitivity δR1 was compared with the physical dose distribution measured with the IC in Supporting Information Figure S2, which shows excellent agreement. N2O Effects: Contribution of eaq− and OH Radical to G(Fe3+). The R1 value of NC-FG saturated with N2O gas was confirmed to exhibit good linearity with respect to ESD at both the entrance surface and the Bragg peak (see Supporting Information Figure S3). Figure 4 compares the radiation

Figure 2. (a) Depth−R1 distribution in an organic-gelatin-free NC-FG dosimeter (deaerated NC-FG). (b) Comparison of the δR 1 distributions with the physical dose distribution (shown on the right vertical axis) measured by the Markus IC under 290 MeV/u carbon ion beam irradiation. The inset in (a) shows the R1 values [s−1] as a function of the ESD [Gy] at the entrance surface (■) and at the Bragg peak (○). The ESD values are 0, 80, 160, 240, and 320 Gy, respectively. Dashed lines indicate repeated experiments in Figure 1b, and these results were obtained by irradiation on different days and by the MRI measurements performed on different postirradiation days.

each penetration depth was confirmed to linearly increase with the absorbed ESD, as shown in the inset of Figure 2a, where the R1 values at the entrance surface and at the Bragg peak are plotted as a function of the ESD. The radiation sensitivity δR1 was evaluated from the slope of the ESD dependence of the R1 value and is plotted as a solid line in Figure 2b, together with the δR1 values obtained from the second experiment performed on June 9, 2015 and the physical dose distribution obtained by the Markus IC. Comparison of the results from the twicerepeated experiments confirmed an excellent reproducibility, except for the data near the Bragg peak. The sensitivity at the entrance surface was δR1 = 1.8 s−1 kGy−1, which is three times higher than that reported previously (0.6 s−1 kGy−1) for NCFG dosimeters containing gelatin.12,13 Using eq 1, we obtained a radiolytic yield G(Fe3+) of 0.19 μmol/J, which is also higher than that reported previously for NC-FG prepared using gelatin.12,13 Furthermore, this δR1 distribution in NC-FG samples could be maintained at least 18 days after irradiation, indicating that the diffusion of Fe3+ is virtually completely suppressed. In addition, the good agreement between the physical dose distribution and the δR1 distribution indicates that the organicgelatin-free NC-FG dosimeter retains the LET-independent dose response of the gelatin-containing NC-FG dosimeter,12,13 whereas most gel dosimeters show decreased sensitivity at the

Figure 4. Comparison of the δR1 distributions of NC-FG using N2O bubbling and deaerated NC-FG shown in Figure 2b. The right vertical axis shows the chemical yield of Fe3+ estimated by eq 1.

sensitivity δR1 as a function of the penetration depth of NC-FG saturated with and without N2O; the oxidation yield is also shown on the right vertical axis. The radiation sensitivity at the entrance surface was 3.9 s−1 kGy−1, increased 2.2-fold by N2O bubbling. On the other hand, LET-dependent sensitivity was observed, as demonstrated by the smaller peak-to-entrance ratio of sensitivity (=3.2) compared to that of deaerated NC-FG (=5.3). 4241

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108 M−1 s−1), that is, only 9% of the OH radicals reacted with H2. Thus, the yield (0.0127 μmol/J or 0.12 s−1 mM−1) of OH scavenging via reaction 5, calculated using the reported G(OH) value (0.13 μmol/J),29 is so small that we cannot definitely identify the possible contribution of H radicals to the oxidation or reduction of iron in NC-FG. In contrast, although molecular hydrogen is the main water radiolysis product under high LET irradiation and accumulates as the absorbed dose in NC-FG gel increases, this experimental result at least provided the information that the molecular hydrogen yield G(H2) does not contribute to the oxidation yield of NC-FG. Oxidation of NC-FG by the Addition of H2O2. The contribution of H2O2 to the oxidation reaction of Fe2+ in NCFG was investigated by the following experiment without the use of radiation. The results of the oxidation of NC-FG by H2O2 are shown in Figure 6 as a plot of the R1 values of NC-FG

The increase in sensitivity is considered to be due to the scavenging of eaq− by N2O N2O + eaq − + H 2O → N2 + OH + OH−

(2)

eaq−

Most of reacted with N2O to form OH radical because N2O has high water solubility (25 mM) and higher reactivity toward eaq− (9.1 × 109 M−1 s−1)27 than Fe2+ in NC-FG (1 mM, 1.2 × 108 M−1 s−1).28 The increase in sensitivity at the entrance surface upon addition of N2O (0.22 μmol/J or 2.1 s−1 kGy−1) is nearly twice higher than the primary yield of eaq− (0.14 μmol/J).29 These observations can be explained by the following stoichiometric chemical equations that take the reduction of Fe3+ by eaq− into account G(Fe3 +)deaerated = G(OH) − G(eaq −) + 2G(H 2O2 ) + G(H) (3)

G(Fe3 +)N2O = G(OH) + G(eaq −) + 2G(H 2O2 ) + G(H) (4) 3+

3+

where G(Fe )deaerated,N2O are the yields of Fe in NC-FG under deaerated conditions and N2O-saturated conditions, respectively. The −G(eaq−) in reaction 3 represents the reduction of Fe3+ by eaq−. The +G(eaq−) in reaction 4 describes the contribution of OH radical produced through reaction 2. The terms 2G(H2O2) + G(H) are discussed in the next section. The possibility of reduction of Fe3+ by eaq− in deaerated solutions at nonacidic pH values was previously pointed out by Matthews.30 H2 Effects: Contribution of H Radical to the Properties of NC-FG. The depth−R1 distributions of NC-FG prepared using H2 bubbling are shown in Supporting Information Figure S4. Figure 5 shows a comparison of the δR1 distributions of

Figure 6. Change in [Fe3+] in NC-FG vs [H2O2] as an additive. Square symbols are data points obtained for nonirradiated NC-FG in the presence of different concentrations of H2O2. The dashed line is a linear fit to the data. The solid line shows simulated results using the Chemsimul kinetics code.

vs the concentration of H2O2. The R1 value linearly increased as the concentration of H2O2 increased. It is known that hydrogen peroxide reacts with ferrous ions and produces OH radicals in an acid Fricke solution H 2O2 + Fe2 + → Fe3 + + OH + OH−

k = 42 M−1 s−1 (6)

OH + Fe

2+

→ Fe

3+

+ OH

−

8

k = 3.4 × 10 M

−1 −1

s

(7)

Because the produced OH radical further oxidizes Fe2+, each H2O2 molecule oxidizes two ferrous ions in total.30−32 However, the slope (1.53) found in Figure 6 is noninteger and smaller than the expected value of 2. Under the conditions of [H2O2] ≫ [Fe2+], according to the Haber−Weiss reaction,33 the amount of hydrogen peroxide decomposed was significantly larger than the amount of Fe3+ formed.34 Therefore, we performed a simulation of the oxidation reaction of Fe2+ by hydrogen peroxide (reactions 6 and 7), including chemical reactions 827 and 9,34 using the chemical kinetics simulator Chemsimul;35 we then compared the simulated results with the experimental results shown in Figure 6. H O + OH → H O + O − + H+ k = 2.7 × 107 M−1 s−1

Figure 5. Comparison of the δR1 distributions of NC-FG using H2 bubbling with the deaerated NC-FG and the repeated experiment shown in Figure 2b.

NC-FG prepared using H2 bubbling and that of deaerated NCFG (shown in Figure 2b). The addition of hydrogen gas seems to have little effect (within 0.2 s−1 kGy−1 except for the Bragg peak region). Hydrogen molecules scavenged OH radicals and produced H radicals as follows H 2 + OH → H + H 2O

k = 4.0 × 107 M−1 s−1

(5)

2

2

2

2

(8)

Thus, the absence of the effect of H2 addition in Figure 5 might suggest that H radicals contribute to the oxidation of Fe2+ just as OH radicals do. It should be noticed, however, that reaction 5 competes with the reaction between Fe2+ and OH radical with an approximately 9 times faster rate constant (3.4 ×

−

O2 + Fe

3+

→ Fe

2+

+ O2

8

k = 1.5 × 10 M

−1 −1

s

(9)

35

From the Chemsimul kinetics code, we understood that 1 mM Fe2+ in NC-FG was completely oxidized by the addition of 4242

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The Journal of Physical Chemistry B 0.55 mM H2O2, as shown by the red line in Figure 6. The slope of the simulated results before saturation of oxidation (0.55 mM H2O2) was 1.85, which is close to 2. However, because the initial concentration of hydrogen peroxide added to NC-FG was over 100 times higher than the simulated concentration (see the Experimental Section), a decrease of the oxidation yield may result from the decomposition of hydrogen peroxide, as shown in reaction 8. In addition, a similar marked loss of stoichiometry has been reported previously for Fricke solutions at natural pH values; the loss was attributed to the addition of H2O2 (∼mM) in great excess of the radiolytic H2O2 yield (∼μM).30 Here, we speculate that the deviation from standard stoichiometry in the present experiment occurs for the same reason; we also assume that the contribution of H2O2 to G(Fe3+) is the same as that in the case of Fricke solutions at natural pH values, that is, 2G(H2O2). Stoichiometric Equations for the Oxidation Yield of Fe3+. It is known that the oxidation yield of Fe2+ can be roughly estimated by substituting the primary yield of water radiolysis products in the stoichiometric equation.36−38 On the basis of the results of the various analyses presented above, we calculated the oxidation yield of Fe3+ in NC-FG under deaerated and N2O-saturated conditions using the stoichiometric reactions 3 and 4 and the primary yield29 of water radiolysis under neutral conditions for carbon ion beam irradiation. Here, we provisionally assumed that the contribution from H is the same as that in deaerated aqueous Fricke solution at natural pH values, that is, +G(H), though we could not obtain conclusive evidence from the results of the experiments with NC-FG prepared using hydrogen bubbling. The primary yields of water radiolysis products change with LET. We fitted the results reported in ref 29 with the following function y = y0 + A1e(−x / t1) + A 2 e(−x / t2)

Figure 7. LET dependence of the calculated chemical oxidation yield G(Fe3+) of NC-FG. Solid lines represent the calculated G(Fe3+) under deaerated and N2O-saturated conditions. Dashed lines represent the calculated G(Fe3+) value under deaerated and N 2O-saturated conditions except for the contribution of G(H).

species, rapidly decrease with an increase in LET due to the recombination of radical species. In the case of NC-FG, the reduction reaction by eaq− and the oxidation reaction by OH radical together compensate for the loss of yield with an increase in LET, thereby contributing largely to the LETindependent dose response of NC-FG. Figure 8 shows a comparison of the calculated and experimental results obtained for the absolute Fe3+ yields. The stacked area charts (a) and (b) were obtained by successively adding up each contribution in reactions 3 and 4, respectively, using the depth-dependent G values shown in

(10)

where x is the LET value (eV/nm) and y is the yield (μmol/J) for each radiolytic product. The obtained fitting parameters are listed in Table 2. Table 2. Fitting Parameters Corresponding to the Primary Yield of Each Water Radiolysis Product as a Function of LET under Carbon Ion Beam Irradiation A1

t1

A2

eaq−

0.006

0.161

9.642

0.106

107.182

OH H H2O2

0.007 0.003 0.144

0.115 0.050 −0.046

20.020 330.208 815.257

0.097 0.022 −0.022

212.350 62.740 17.286

species

y0

t2

G(Fe3+)deaerated,N2O values given by reactions 3 and 4 are plotted as a function of LET in Figure 7, where the lower and upper limits of LET correspond to the entrance surface and the Bragg peak, respectively, for 12C 6+ 290 MeV/u beam irradiation.8 Whereas the calculated G(Fe3+)N2O decreased by a factor of 2 with an increase in LET, the calculated G(Fe3+)deaerated was essentially independent of LET. This explains why the NC-FG dosimeter reproduces the physical dose distribution of a heavy ion beam, free from LET dependence. In general, the radiation sensitivity of a conventional FG or aqueous Fricke solution decreases with an increase in LET value because G(OH) and G(eaq−), the main radical

Figure 8. (a,b) Stacked area chart of calculated G(Fe3+) at (a) deaerated or (b) N2O-saturated conditions for each primary radical product together with the measured G(Fe3+) (square symbols + line) as a function of penetration depth. (c) Calculated primary radical yield (solid line) per ESD with the reported LET values8 (dashed line, right vertical axis) as a function of penetration depth. 4243

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selenate (7 mM) addition increases the sensitivity to almost the same level as the N2O-saturated sample. Below, we show the reported eaq− scavenging reactions of nitrate and selenate42,44

Figure 8c. The simulated yields are in rough agreement with the experimental yields, though the former are approximately 0.1 μmol/J higher than the latter. This is the first report of a quantitative comparison of the sensitivity of gel dosimeters that takes into account the yields of individual water radiolysis products. In conventional gel dosimetry,4,5 such quantitative evaluation is difficult due to complex chain reactions involving the reaction of water radiolysis radicals with organic gelling agents. We have assumed that the consumption of radical species due to reactions (except for reactions with Fe3+ or Fe2+) is negligible for the following two reasons. First, NC-FG has a very simple composition: water, ferrous ion, and nanoclay. Second, the reactivity of nanoclay with radical species is considerably lower than that of the ferrous ion.39 Interestingly, in Figure 8, we notice that the calculated value shows even better agreement with the experimental results if the contribution of H radicals G(H) is eliminated from reactions 3 and 4, though G(Fe3+) slightly increases with an increase in LET in this case (black dashed line in Figure 7). H radicals may contribute to both reduction and oxidation, in the same way as they do in a deaerated neutral pH Fricke solution,30 leading to a vanishing contribution of H radicals. Further investigation will be necessary to reveal the redox reactions of H radicals in NC-FG. In addition, the iron oxidation yields shown in Figure 7 and 8 were obtained by a simplified model. To obtain more details, we would need to perform these calculations using nonhomogeneous chemistry code that considers the ion beam track structure, such as PARTRAC,40 IONLYS-IRT,36 and so forth.41 Effects of the Addition of NO3−, SeO42−, and Cd2+ (eaq− Scavengers). The results of the N2O effects discussed above indicated that eaq− contributes to the reduction of Fe3+ in NCFG under a deaerated condition (reaction 3). Therefore, we may expect that the removal of eaq− by scavengers will eventually cause an increase in the oxidation yield of Fe2+ to a value between G(Fe3+)deaerated and G(Fe3+)N2O (see reactions 3 and 4). In order to verify this speculation, we investigated the effects of the addition of nitrate, selenate, and cadmium, which are well-known electron scavengers and were used in water radiolysis studies;42,43 their scavenging capacities [s−1] are summarized in Table 1. From the depth−R1 distribution of NC-FG containing electron scavengers, as shown in Supporting Information Figure S5, a linear increase in R1 values with an increase in the ESD was observed for all conditions. The sensitivities of NC-FG for each condition are plotted in Figure 9 along with the results obtained with deaerated samples or N2O-saturated samples. Surprisingly, nitrate (1 mM) or

NO3− + eaq − → NO3•2 −( +H 2O) → 2OH− + NO2• (11)

SeO4 2 − + eaq −( +H 2O) → 2OH− + SeO3•−

(12)

The intermediate radicals NO2• and SeO3•− are known to be oxidizing agents and have a positive redox potential.45,46 It was also reported previously that SeO3•− oxidizes ferrocyanide (containing Fe2+) to ferricyanide (containing Fe3+).47 Hence, these intermediate radicals may also oxidize Fe2+, which may explain the above results. On the other hand, the addition of cadmium did not change the radiation sensitivity of NC-FG. Cd2+ has the highest eaq− scavenging capacity of the three scavengers tested, as shown in Table 1, and thus we expected that Cd2+ would also react with eaq− as follows48 Cd2 + + eaq − → Cd+

(13)

The resulting Cd+ is still regarded as a reducing agent and can be recycled back to Cd2+ by reaction with another Cd+ or with oxidants (OX) as follows45 Cd+ + OX → Cd2 + + OX−

(14)

Fe3+ may have been reduced via this reaction, canceling the effect of the eaq− decrease. In addition to the redox properties of the intermediate radicals, the adsorption effects of the added radical scavengers may also influence the oxidation yield of Fe2+, which requires further studies.

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CONCLUSIONS

We have demonstrated an LET-independent NC-FG dosimeter with radiation sensitivity (1.8 s−1 kGy−1) 3 times higher than that of the previously reported NC-FG prepared with gelatin. This improvement was achieved by eliminating gelatin. This gel, called an organic-gelatin-free NC-FG, is a thixotropic hydrogel prepared using a rotation/revolution mixer from only Fe2+ and nanoclay in water at neutral pH. The Fe3+ yield of NC-FG was determined to be 0.19 μmol/J, independent of LET, dose rate, and dose fractionation, under carbon ion beam irradiation. We have found that the addition of N2O gas leads to further increase in radiation sensitivity, indicating a reduction reaction of Fe3+ by eaq−. The contribution of the main water radiolysis products on the performance of NC-FG was revealed and the stoichiometric equation {G(Fe3+) = G(OH) − G(eaq−) + 2G(H2O2) + G(H)} was proposed. Although the influence of H radical, being minor anyway, is not totally clear, this equation not only reproduces the experimentally determined G(Fe3+) value but also reveals that the key mechanism underlying the LET-independent dose response of NC-FG is the reduction reaction by eaq−. Investigation of the effects of eaq− scavengers (nitrate, selenate, and cadmium) implies that intermediate radicals produced after the eaq− scavenging might affect the redox reaction of NC-FG.

Figure 9. Comparison of the δR 1 distributions of NC-FG incorporating eaq− scavengers (1 mM NO3−, 1 mM Cd2+, 1 mM SeO42−, or 7 mM SeO42−) and deaerated or N2O-saturated NC-FG. 4244

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(12) Maeyama, T.; Fukunishi, N.; Ishikawa, K. L.; Furuta, T.; Fukasaku, K.; Takagi, S.; Noda, S.; Himeno, R.; Fukuda, S. A diffusionfree and linear-energy-transfer-independent nanocomposite Fricke gel dosimeter. Radiat. Phys. Chem. 2014, 96, 92−96. (13) Maeyama, T.; Fukunishi, N.; Ishikawa, K. L.; Fukasaku, K.; Fukuda, S. Radiological properties of nanocomposite Fricke gel dosimeters for heavy ion beams. J. Radiat. Res. 2016, 57, 318−24. (14) Appleby, A.; Leghrouz, A.; Christman, E. A. Radiation chemical and magnetic resonance studies of aqueous agarose gels containing ferrous ions. Int. J. Radiat. Appl. Instrum. C Radiat. Phys. Chem. 1988, 32, 241−244. (15) Schulz, R. J.; Deguzman, A. F.; Nguyen, D. B.; Gore, J. C. Doseresponse curves for Fricke-infused agarose gels as obtained by nuclear magnetic resonance. Phys. Med. Biol. 1990, 35, 1611−1622. (16) Olsson, L. E.; Appleby, A.; Sommer, J. A new dosimeter based on ferrous sulphate solution and agarose gel. Int. J. Radiat. Appl. Instrum. Part A, Appl. Radiat. Isot. 1991, 42, 1081−1086. (17) Keller, B. M. Characterization of the NMR-Based Fricke-Gelatin Dosimeter. M.D. Thesis, McGill University, Canada, 1994. (18) Kanai, T.; Fukumura, A.; Kusano, Y.; Shimbo, M.; Nishio, T. Cross-calibration of ionization chambers in proton and carbon beams. Phys. Med. Biol. 2004, 49, 771−781. (19) Torikoshi, M.; Minohara, S.; Kanematsu, N.; Komori, M.; Kanazawa, M.; Noda, K.; Miyahara, N.; Itoh, H.; Endo, M.; Kanai, T. Irradiation system for HIMAC. J. Radiat. Res. 2007, 48, A15−A25. (20) Minohara, S.; Fukuda, S.; Kanematsu, N.; Takei, Y.; Furukawa, T.; Inaniwa, T.; Matsufuji, N.; Mori, S.; Noda, K. Recent innovations in carbon-ion radiotherapy. J. Radiat. Res. 2010, 51, 385−392. (21) Kanai, T.; Endo, M.; Minohara, S.; Miyahara, N.; Koyama-Ito, H.; Tomura, H.; Matsufuji, N.; Futami, Y.; Fukumura, A.; Hiraoka, T.; et al. Biophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy. Int. J. Radiat. Oncol., Biol., Phys. 1999, 44, 201−210. (22) Hojo, S.; Katagiri, K.; Nakao, M.; Sugiura, A.; Muramatsu, M.; Noda, A.; Okada, T.; Takahashi, Y.; Komiyama, A.; Honma, T.; et al. Present status of cyclotrons (NIRS-930, HM-18) in NIRS (in Japanese). Proceedings of the 10th Annual Meeting of Particle Accelerator Society of Japan, Nagoya, Japan, August 3−5, 2013; http://www.pasj. jp/web_publish/pasj10/proceedings/PDF/SSFP/SSFP14.pdf. (23) Baldock, C.; Burford, R. P.; Billingham, N.; Wagner, G. S.; Patval, S.; Badawi, R. D.; Keevil, S. F. Experimental procedure for the manufacture and calibration of polyacrylamide gel (PAG) for magnetic resonance imaging (MRI) radiation dosimetry. Phys. Med. Biol. 1998, 43, 695−702. (24) in den Kleef, J. J. E.; Cuppen, J. J. M. RLSQ: T1, T2, and ρ calculations, combining ratios and least squares. Magn. Reson. Med. 1987, 5, 513−524. (25) Prasad, P. V.; Nalcioglu, O.; Rabbani, B. Measurement of threedimensional radiation dose distributions using MRI. Radiat. Res. 1991, 128, 1−13. (26) Audet, C.; Schreiner, L. J. Multiple-site fast exchange model for spin-lattice relaxation in the Fricke-gelatin dosimeter. Med. Phys. 1997, 24, 201−9. (27) Buxton, G. V.; Greenstock, C. L.; Helman, W. P.; Ross, A. B. Critical review of rate constants for reactions of hydrated electrons, hydrogen atoms and hydroxyl radicals (•OH/•O−) in aqueous solution. J. Phys. Chem. Ref. Data 1988, 17, 513−886. (28) Bjergbakke, E.; Dragarne, Z. D.; Sehested, K.; Dragarne, I. G. Radiolytic products in waters. part 1: computer simulation of some radiolytic processes in the laboratory. Radiochim. Acta 1989, 48, 65− 71. (29) Meesungnoen, J.; Jay-Gerin, J. P. High-LET Radiolysis of liquid water with 1H+, 4He2+, 12C6+, and 20Ne9+ ions: Effects of multiple ionization. J. Phys. Chem. A 2005, 109, 6406−6419. (30) Matthews, R. W. The radiation chemistry of aqueous ferrous sulfate solutions at natural pH. Aust. J. Chem. 1983, 36, 1305−1317. (31) Fricke, H.; Hart, E. J. Chemical Dosimetry. In Radiation Dosimetry: Instrumentation; Attix, F. H., Roesch, W. C., Tochilin, E., Eds.; Academic Press: New York, 1966; Chapter 12, pp 167−239.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.6b11936. Additional results, such as measurements concerning the R1 map, depth−R1 distribution of NC-FG under several preparation conditions, and a comparison of the δR1 distribution for the NC-FG and the IC dose distribution (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Telephone: +81-42-7788159. ORCID

Takuya Maeyama: 0000-0003-2850-3331 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was carried out as a Research Project with Heavy Ions at NIRS-HIMAC. T.M. gratefully acknowledges support from the RIKEN Special Postdoctoral Researchers Program and JSPS KAKENHI Grant Numbers 26820412, 24760725, 26460736.

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REFERENCES

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